# ent

id: cord-001961-0ic7twhy
type: PROTEIN
entity:
  angiotensin converting enzyme 2 angiotensin 1 7 Mas axis Angiotensin converting enzyme 2 angiotensin 1 7


id: cord-001961-0ic7twhy
type: GO
entity:
  basement membrane arteriolar hyalinosis and tubulointerstitial fibrosis 17 An ideal model of DN would


id: cord-006439-q7m4srvp
type: DNA
entity:
  bacterial artificial chromosome transgenic AT 2 R enhanced green fluorescent protein eGFP reporter mouse


id: cord-006439-q7m4srvp
type: WORK_OF_ART
entity:
  The Renin Angiotensin System in the Central Nervous System and Its Role in Blood Pressure Regulation date 2020 01 10


id: cord-276260-iccaqz8u
type: GGP
entity:
  transforming growth factor beta receptor II AT 1 R angiotensin II type 1 receptor RTKs receptor tyrosine kinases Akt protein kinase B PTP protein tyrosine phosphatase PSP protein serine threonine


id: cord-276260-iccaqz8u
type: GGP
entity:
  Angiotensin II type 2 receptor MasR Mas receptor ARB Angiotensin II type 1 receptor blocker ACE Angiotensin converting enzyme


id: cord-289905-dvl2pud2
type: PROTEIN
entity:
  Renin Angiotensin System RAS T Unger UM Steckelings and RAS dos Santos Are patients with hypertension and diabetes mellitus


id: cord-007707-c38fu1jv
type: DISEASE
entity:
  human immunodeficiency virus HIV 1 parvovirus B19 cytomegalovirus CMV hepatitis B virus HBV and hepatitis C virus HCV


id: cord-277766-rxmpi61o
type: CHEBI
entity:
  l angiotensine 2 angiotensine 1 MAS l AC2 contrebalance l effet vasoconstricteur prolifératif fibrosant et pro inflammatoire


id: cord-277766-rxmpi61o
type: CHEMICAL
entity:
  tetrapeptide N acetyl Ser Asp Lys Pro on the G1 S transition of rat hepatocytes The tetrapeptide AcSDKP


id: cord-277766-rxmpi61o
type: CHEMICAL
entity:
  angiotensinconverting enzyme 2 ACE2 gene polymorphisms with parameters of left ventricular hypertrophy


id: cord-272546-zznm13ik
type: CELL_LINE
entity:
  EACTA Thoracic Subspecialty Committee Lung injury after one lung ventilation a review of the pathophysiologic mechanisms affecting the ventilated and the collapsed lung Covid 19


id: cord-298490-p1msabl5
type: ORG
entity:
  the American College of Cardiology American Heart Association American Society of Hypertension and European Heart Association


id: cord-280662-gakayv6e
type: PROTEIN
entity:
  China 91939301 81820108031 91539123 and 81471893 and Beijing Municipal Natural Science Foundation 7172235 China


id: cord-280662-gakayv6e
type: GGP
entity:
  SARS CoV 2 receptors monomer receptor homodimer receptor alternative receptors co receptors and transmissive receptor


id: cord-280662-gakayv6e
type: GGP
entity:
  SARS CoV 2 monomer receptor homodimer receptor alternative receptors co receptors and transmissive receptor


id: cord-280662-gakayv6e
type: GGP
entity:
  human angiotensin converting enzyme related carboxypeptidase MAS axis of the renin angiotensin system focus on angiotensin Angiotensin 1 7


id: cord-280662-gakayv6e
type: DISEASE
entity:
  nasal mucosa nasopharynx lung stomach small intestine colon skin lymph nodes thymus bone marrow spleen liver kidney


id: cord-317423-3nkzp1z2
type: PROTEIN
entity:
  ACE2 angiotensin converting enzyme ACE insulinlike growth factor 2 receptor IGF2R angiotensinogen AGT epidermal growth factor receptor EGFR


id: cord-303555-mwu72q7w
type: GGP
entity:
  RAF 1 serine threonine kinase most closely resembled the active sites of SRC family non receptor tyrosine kinases


id: cord-303555-mwu72q7w
type: FAC
entity:
  Hepatocytes Ligand Mediated Internalization Recycling and Downregulation of the Epidermal Growth Factor Receptor


id: cord-303555-mwu72q7w
type: ORG
entity:
  the Use and Interpretation of Assays for Monitoring Autophagy Evolution of Tools and Methods for Monitoring Autophagic Flux


id: cord-303555-mwu72q7w
type: WORK_OF_ART
entity:
  The Tale of a Repented Natural Born Killer OSU 03012 Stimulates PKR Like Endoplasmic Reticulum Dependent Increases


id: cord-324364-9p04oeac
type: GGP
entity:
  ACEIs ARBs Supplementary 35 36 54 59 66 67 69 70 72 74 78 80 86 88 92 93 Representativeness of the exposed cohort could not be established in 16 studies 36 54 56 57 59 64 67 69 72 74 81 86 88 89 92 93 that included hospitalized patients only In 13 studies 35 59 67 72 74 76 78 80 81 86 88 93 it was unclear whether the entire


id: cord-324364-9p04oeac
type: GGP
entity:
  ACEIs ARBs Supplementary Table S1 Of the 16 original studies included only one study by Zhang et al 56


id: cord-351875-e4aw7gkd
type: GGP
entity:
  ARB angiotensin II receptor blocker AT1 angiotensin 1 PCR polymerase chain reaction RAS renin angiotensin


id: cord-311099-59pnm4fn
type: CHEMICAL
entity:
  angiotensin 1 7 metabolism in pulmonary and renal tissues Angiotensin 1 7 reduces bile duct proliferation and hepatic fibrosis


id: cord-328846-q52fjx99
type: CELL_TYPE
entity:
  Smooth Muscle Cells Maintains Genome Integrity Resists Aortic Medial Degeneration and Is Suppressed in Human Thoracic Aortic Aneurysm Disease Alpha7 Nicotinic Acetylcholine Receptor Relieves Angiotensin II


id: cord-328846-q52fjx99
type: WORK_OF_ART
entity:
  Vascular ADAM17 as a Novel Therapeutic Target in Mediating Cardiovascular Hypertrophy and Perivascular Fibrosis Induced by


id: cord-328846-q52fjx99
type: ORG
entity:
  angiotensin II Smooth Muscle Cell Stiffness Syndrome Revisiting the Structural Basis of Arterial Stiffness Proinflammatory Arterial Stiffness Syndrome A Signature of Large Arterial Aging Establishment of Novel Murine Model


id: cord-318327-9sh2eksm
type: CELL_LINE
entity:
  rat brush border epithelial cells lamina propria muscularis mucosa submucosal blood vessels and muscularis propria 77 Angiotensinogen mRNA


id: cord-318327-9sh2eksm
type: GGP
entity:
  endopeptidase Am aminopeptidase AT1R angiotensin type 1 receptor AT2R angiotensin type 2 receptor AT4R angiotensin type 4 receptor PRR pro renin receptor water


id: cord-352854-che3iwu3
type: PROTEIN
entity:
  C terminal modi cations Lane 1 ras WT CAAX Lane 2 ras 61L CAAX Lane 3 ras 61L 3S Lane 4 E1 3 ras WT 3S Lane 5 E1 QI 3 ras WT SAAX Lane 6 E1 11 ras WT SAAX Lane 7 E1 QI 11 ras 61L 3S Lane 8 E1 22 ras WT SAAX Lane 9 E1 QI 22 ras 61L


id: cord-352854-che3iwu3
type: CHEMICAL
entity:
  Kristen C Donoghue Daniel J title Derivatives of activated H ras lacking C terminal lipid modifications


id: cord-344012-npob20n0
type: CHEMICAL
entity:
  angiotensin 1 7 levels respectively Our review summarizes the progress over the past 20 years highlighting


id: cord-313664-qq0h68vc
type: GGP
entity:
  Ang 1 7 AT2R angiotensin type 2 receptor AT1R angiotensin type 1 receptor IRAP insulin regulated aminopeptidase Ang IV receptor AMPA aminopeptidase A AMPM aminopeptidase M ACE angiotensin converting enzyme ACE2 angiotensin converting enzyme


id: cord-326498-8oa5gkrp
type: GGP
entity:
  human ACE2 rhACE2 68 69 70 Intuitively this strategy could also be a possible treatment for COVID 19


id: cord-317878-bqpj0ey0
type: DISEASE
entity:
  acute respiratory distress syndrome Acute respiratory distress syndrome Acute respiratory distress syndrome


id: cord-349445-yh6ndtgm
type: PROTEIN
entity:
  Transforming Growth Factor β1 Induced Endothelial To Mesenchymal Transition and Tissue Fibrosis by Endothelin 1 ET 1 A


id: cord-349445-yh6ndtgm
type: PROTEIN
entity:
  Angiotensin Converting Enzyme 2 Angiogenesis 1 7 Mas Axis Confers Cardiopulmonary Protection against Lung Fibrosis and Pulmonary Hypertension


id: cord-349445-yh6ndtgm
type: GGP
entity:
  ACE 2 Angiotensin converting enzyme 2 Ang 1 7 Angiotensin AT 1 Angiotensin II type 1 receptor ET 1 Endothelin 1 fMLP


id: cord-349445-yh6ndtgm
type: ORG
entity:
  Interleukin 6 Induces Oxidative Stress and Endothelial Dysfunction by Overexpression of the Angiotensin II Type 1 Receptor Endothelium


id: cord-349445-yh6ndtgm
type: ORG
entity:
  Structural Substrate Conditions Required for Neutral Endopeptidase Mediated Natriuretic Peptide Degradation


id: cord-349445-yh6ndtgm
type: LAW
entity:
  ARNIs COVID 19 Treatment Close to a Cure A Rapid Review of Pharmacotherapies for the Novel Coronavirus Risks Related to the Use of Non Steroidal Anti Inflammatory Drugs in Community Acquired Pneumonia in Adult and Pediatric Patients


# bib

id: cord-001961-0ic7twhy
author: Ding, Dan
date: 2015-09-26
txt: ./txt/cord-001961-0ic7twhy.txt
cache: ./cache/cord-001961-0ic7twhy.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762923/
doi: 10.1007/s00109-015-1343-6
summary:
  In addition to lower blood pressure, ATRQβ-001 vaccination ameliorated biochemical parameter changes of renal dysfunction, mesangial expansion, and fibrosis through inhibiting oxidative stress, macrophage infiltration, and proinflammatory factor expression. Furthermore, ATRQβ-001 vaccination suppressed renal Ang II-AT1R activation and abrogated the downregulation of angiotensin-converting enzyme 2-Ang (1–7), similar to olmesartan treatment, while no obvious feedback activation of circulating or local renin-angiotensin system (RAS) was only observed in vaccine group. In conclusion, the ATRQβ-001 vaccine ameliorated streptozotocin-induced diabetic renal injury via modulating two RAS axes and inhibiting TGF-β1/Smad3 signal pathway, providing a novel, safe, and promising method to treat diabetic nephropathy. Recently, we developed a therapeutic hypertensive vaccine ATRQβ-001, a peptide (ATR-001) derived from human Ang II receptor type 1 (AT1R) conjugated with Qβ bacteriophage virus-like particles, which decreased the blood pressure of hypertensive animals effectively through diminishing the pressure response and inhibiting signal transduction initiated by Ang II with no obvious feedback activation of circulating or local RAS [11] .

title:
  Vaccination against type 1 angiotensin receptor prevents streptozotocin-induced diabetic nephropathy

abstract:
  ABSTRACT: Recently, our group has developed a therapeutic hypertensive vaccine against angiotensin (Ang) II type 1 receptor (AT1R) named ATRQβ-001. To explore its potential effectiveness on streptozotocin-induced diabetic nephropathy, male Sprague Dawley rats were randomly divided into two groups: a control and a diabetic model. After 1 week, the diabetic rats were divided into four subgroups (each with 15 rats) for 14-week treatments with saline, olmesartan, ATRQβ-001, and Qβ virus-like particle (VLP), respectively. In addition to lower blood pressure, ATRQβ-001 vaccination ameliorated biochemical parameter changes of renal dysfunction, mesangial expansion, and fibrosis through inhibiting oxidative stress, macrophage infiltration, and proinflammatory factor expression. Furthermore, ATRQβ-001 vaccination suppressed renal Ang II-AT1R activation and abrogated the downregulation of angiotensin-converting enzyme 2-Ang (1–7), similar to olmesartan treatment, while no obvious feedback activation of circulating or local renin-angiotensin system (RAS) was only observed in vaccine group. In rat mesangial cells, the anti-ATR-001 antibody inhibited high glucose-induced transforming growth factor-β1 (TGF)-β1/Smad3 signal pathway. Additionally, no significant immune-mediated damage was detected in vaccinated animals. In conclusion, the ATRQβ-001 vaccine ameliorated streptozotocin-induced diabetic renal injury via modulating two RAS axes and inhibiting TGF-β1/Smad3 signal pathway, providing a novel, safe, and promising method to treat diabetic nephropathy. KEY MESSAGES: Overactivation of RAS plays a crucial role in the development of the DN. Our aim was to verify the effectiveness of ATRQβ-001 vaccine in STZ-induced DN. The ATRQβ-001 modulated two RAS axes and inhibited TGF-β1/Smad3 signal pathway. The vaccine therapy may provide a novel, safe, and promising method to treat DN. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00109-015-1343-6) contains supplementary material, which is available to authorized users.


id: cord-002632-6he8sjpf
author: Goldstein, Benjamin
date: 2017-07-16
txt: ./txt/cord-002632-6he8sjpf.txt
cache: ./cache/cord-002632-6he8sjpf.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534309/
doi: 10.1155/2017/6914976
summary:
  There were a number of profound differences in the expression of the genes encoding the proteins comprising and closely associated with the renin-angiotensin system (RAS), between normal lung tissue and the lung tumor tissue (Figures 1 and 2 and Table 2 ). The gene expression for both Ang II receptor subtypes was dramatically reduced, 69 and 74%, respectively, ( Figure S1 ), for AT 1 and AT 2 in the lung tumor tissue ( < 0.01, corrected for multiple comparisons, Table 2 ). ACE, the gene that encodes the enzyme that converts the inactive precursor angiotensin I (Ang I) to the active hormone, Ang II, was expressed at a lower level and its expression was reduced by about half in the lung tumor tissue ( < 0.01 corrected for multiple comparisons Table 2 ).

title:
  Alterations in Gene Expression of Components of the Renin-Angiotensin System and Its Related Enzymes in Lung Cancer

abstract:
  OBJECTIVES: The study assessed the existence and significance of associations between the expression of fifteen renin-angiotensin system component genes and lung adenocarcinoma. MATERIALS AND METHODS: NCBI's built-in statistical tool, GEO2R, was used to calculate Student's t-tests for the associations found in a DNA expression study of adenocarcinoma and matched healthy lung tissue samples. The raw data was processed with GeneSpring™ and then used to generate figures with and without Sidak's multiple comparison correction. RESULTS: Ten genes were found to be significantly associated with adenocarcinoma. Seven of these associations remained statistically significant after correction for multiple comparisons. Notably, AGTR2, which encodes the AT(2) angiotensin II receptor subtype, was significantly underexpressed in adenocarcinoma tissue (p < 0.01). AGTR1, ACE, ENPEP, MME, and PRCP, which encode the AT(1) angiotensin II receptor, angiotensin-converting enzyme, aminopeptidase N, neprilysin, and prolylcarboxypeptidase, respectively, were also underexpressed. AGT, which encodes angiotensinogen, the angiotensin peptide precursor, was overexpressed in adenocarcinoma tissue. CONCLUSION: The results suggest an association between the expression of the genes for renin-angiotensin system-related proteins and adenocarcinoma. While further research is necessary to conclusively demonstrate a link between the renin-angiotensin system and lung cancers, the results suggest that the renin-angiotensin system plays a role in the pathology of adenocarcinoma.


id: cord-005931-iggkxbbf
title: Brain renin angiotensin in disease
author: Phillips, M. Ian
date: 2008-04-02
txt: ./txt/cord-005931-iggkxbbf.txt
cache: ./cache/cord-005931-iggkxbbf.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095973/
doi: 10.1007/s00109-008-0331-5
summary:
  Transgenic mice and rats bearing renin and extra copies of angiotensinogen genes revealed the importance of brain RAS. Taking the concept a step further, it was reasoned that if ANG II, formed by brain renin, was involved in hypertension, then inhibiting brain RAS would lower blood pressure. Minute injections of ANG II into key brain nuclei showed that ANG II could differentially produce pressor effects, elicit drinking, release vasopressin, inhibit the baroreflex, and increase sympathetic nervous system activity [20, 21] . In the double transgenic mice developed by Sigmund and colleagues [35] , to overexpress both human renin and human AGT so that they constantly have high ANG II levels, antisense to AT1R mRNA dramatically reduced the blood pressure. ACE-2, ANG (1-7), and Mas receptors are all localized in brain areas related to the control of cardiovascular function.

abstract:
  A brain renin angiotensin system (RAS) and its role in cardiovascular control and fluid homeostasis was at first controversial. This was because a circulating kidney-derived renin angiotensin system was so similar and well established. But, the pursuit of brain RAS has proven to be correct. In the course of accepting brain RAS, high standards of proof attracted state of the art techniques in all the new developments of biolo1gy. Consequently, brain RAS is a robust concept that has enlightened neuroscience as well as cardiovascular physiology and is a model neuropeptide system. Molecular biology confirmed the components of brain RAS and their location in the brain. Transgenic mice and rats bearing renin and extra copies of angiotensinogen genes revealed the importance of brain RAS. Cre-lox delivery in vectors has enabled pinpoint gene deletion of brain RAS in discrete brain nuclei. The new concept of brain RAS includes ACE-2, Ang1–7, and prorenin and Mas receptors. Angiotensin II (ANG II) generated in the brain by brain renin has many neural effects. It activates behavioral effects by selective activation of ANG II receptor subtypes in different locations. It regulates sympathetic activity and baroreflexes and contributes to neurogenic hypertension. New findings implicate brain RAS in a much wider range of neural effects. We review brain RAS involvement in Alzheimer’s disease, stroke memory, and learning alcoholism stress depression. There is growing evidence to consider developing treatment strategies for a variety of neurological disease states based on brain RAS.


id: cord-006439-q7m4srvp
author: Nakagawa, Pablo
date: 2020-01-10
txt: ./txt/cord-006439-q7m4srvp.txt
cache: ./cache/cord-006439-q7m4srvp.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101821/
doi: 10.1007/s11906-019-1011-2
summary:
  Central administration of ANG-II elicits potent dipsogenic responses, induces sodium intake, triggers sympathetic outflow to the kidney and other organs, and recently, evidence has established that the brain RAS modulates metabolic function primarily through distinct nuclei within the hypothalamus [14] [15] [16] [17] . In the final section of this article, we will discuss how the development of state-of-the-art technology to study precise molecular signaling and neuronal circuits within the CNS are appropriate to elucidate the key mechanisms regulating generation and action of angiotensin peptides within different neuroanatomical regions. Intracerebroventricular infusion of ACE inhibitor prevents and reverses high blood pressure, demonstrating that production of ANG-II in the brain is required for DOCA-salt hypertension even though circulating RAS activity is suppressed [71] . Therefore, the development of novel drugs modulating the brain RAS might represent an effective solution to treat resistant hypertension coincident with elevated sympathetic activity and suppressed circulating renin activity.

title:
  The Renin-Angiotensin System in the Central Nervous System and Its Role in Blood Pressure Regulation

abstract:
  PURPOSE OF THE REVIEW: The main goal of this article is to discuss how the development of state-of-the-art technology has made it possible to address fundamental questions related to how the renin-angiotensin system (RAS) operates within the brain from the neurophysiological and molecular perspective. RECENT FINDINGS: The existence of the brain RAS remains surprisingly controversial. New sensitive in situ hybridization techniques and novel transgenic animals expressing reporter genes have provided pivotal information of the expression of RAS genes within the brain. We discuss studies using genetically engineered animals combined with targeted viral microinjections to study molecular mechanisms implicated in the regulation of the brain RAS. We also discuss novel drugs targeting the brain RAS that have shown promising results in clinical studies and trials. SUMMARY: Over the last 50 years, several new physiological roles of the brain RAS have been identified. In the coming years, efforts to incorporate cutting-edge technologies such as optogenetics, chemogenetics, and single-cell RNA sequencing will lead to dramatic advances in our full understanding of how the brain RAS operates at molecular and neurophysiological levels.


id: cord-006737-7h8vvim7
author: Chen, Xiang-Fan
date: 2018-02-07
txt: ./txt/cord-006737-7h8vvim7.txt
cache: ./cache/cord-006737-7h8vvim7.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102314/
doi: 10.1016/j.pharep.2018.02.008
summary:
  BACKGROUND: This study aimed to study the osteo-preservative effects of captopril, an inhibitor on angiotensin-converting enzyme (ACE), on bone mass, micro-architecture and histomorphology as well as the modulation of captopril on skeletal renin-angiotensin system (RAS) and regulators for bone metabolism in mice with bilateral orchidectomy. The mRNA expressions of renin receptor, angiotensinogen, carbonic anhydrase II, matrix metalloproteinase-9, and tumor necrosis factor-alpha were significantly decreased in tibia of ORX mice following treatment with captopril. This study demonstrated that the treatment with captopril effectively attenuated the orchidectomy-induced pathological alterations of micro-structure of trabecular bone at lumbar vertebra (LV)-4, distal metaphysis of femur and proximal metaphysis of tibia as observed by histological staining, moreover, bone mineral density (BMD) at both LV-2 and LV-5 was significantly enhanced in ORX mice in response to captopril treatment for 6 weeks. This study demonstrated that captopril effectively reversed orchidectomy-induced down-regulation of B1R protein expression in mice, indicating that bradykinin receptor was involved in management of captopril on bone metabolism in ORX mice.

title:
  Inhibition on angiotensin-converting enzyme exerts beneficial effects on trabecular bone in orchidectomized mice

abstract:
  BACKGROUND: This study aimed to study the osteo-preservative effects of captopril, an inhibitor on angiotensin-converting enzyme (ACE), on bone mass, micro-architecture and histomorphology as well as the modulation of captopril on skeletal renin-angiotensin system (RAS) and regulators for bone metabolism in mice with bilateral orchidectomy. METHODS: The orchidectomized (ORX) mice were orally administered with vehicle or captopril at low dose (10 mg/kg) and high dose (50 mg/kg) for six weeks. The distal femoral end, the proximal tibial head and the lumbar vertebra (LV) were stained by hematoxylin and eosin, Safranin O/Fast Green and masson-trichrome. Micro-computed tomography was performed to measure bone mineral density (BMD). RESULTS: Treatment with captopril increased trabecular bone area at distal metaphysis of femur, proximal metaphysis of tibia and LV-4, moreover, high dose of captopril significantly elevated trabecular BMD of LV-2 and LV-5. The mRNA expressions of renin receptor, angiotensinogen, carbonic anhydrase II, matrix metalloproteinase-9, and tumor necrosis factor-alpha were significantly decreased in tibia of ORX mice following treatment with captopril. The administration with captopril enhanced the ratio of OPG/RANKL mRNA expression, the mRNA expression of transforming growth factor-beta and the protein expression of bradykinin receptor-1. CONCLUSIONS: The inhibition on ACE by captopril exerts beneficial effects on trabecular bone of ORX mice. The therapeutic efficacy may be attributed to the regulation of captopril on local RAS and cytokines in bone.


id: cord-007707-c38fu1jv
title: Role of Podocyte Injury in Glomerulosclerosis
author: Lu, Chen-Chen
date: 2019-06-19
txt: ./txt/cord-007707-c38fu1jv.txt
cache: ./cache/cord-007707-c38fu1jv.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7120923/
doi: 10.1007/978-981-13-8871-2_10
summary:
  Increased intracellular glucose could induce multiple cell and molecular events in podocyte: (1) generation of reactive oxygen species (ROS) and advanced glycation end products (AGEs), (2) increased flux of polyols and hexosamines, (3) activation of protein kinase C (PKC), (4) increased cytokines and growth factors, (5) aberrant Notch signaling, and (6) activate the renal RAS. High glucose induces generation of advanced glycation end products (AGEs) and reactive oxygen species (ROS), increased flux of polyols and hexosamines, increased activity of protein kinase C (PKC), upregulated expression of cytokines and growth factors including vascular endothelial growth factor (VEGF), and transforming growth factor-beta (TGF-β), induces aberrant Notch signaling, and activates the renal RAS (Anil Kumar et al. (2013) findings elaborated that Rac1/PAK1 signaling contributed to high glucose-induced podocyte EMT via promoting β-catenin and Snail transcriptional activities, which could be a potential mechanism involved in podocytes injury in response to stimuli under diabetic conditions.

abstract:
  Finding new therapeutic targets of glomerulosclerosis treatment is an ongoing quest. Due to a living environment of various stresses and pathological stimuli, podocytes are prone to injuries; moreover, as a cell without proliferative potential, loss of podocytes is vital in the pathogenesis of glomerulosclerosis. Thus, sufficient understanding of factors and underlying mechanisms of podocyte injury facilitates the advancement of treating and prevention of glomerulosclerosis. The clinical symptom of podocyte injury is proteinuria, sometimes with loss of kidney functions progressing to glomerulosclerosis. Injury-induced changes in podocyte physiology and function are actually not a simple passive process, but a complex interaction of proteins that comprise the anatomical structure of podocytes at molecular levels. This chapter lists several aspects of podocyte injuries along with potential mechanisms, including glucose and lipid metabolism disorder, hypertension, RAS activation, micro-inflammation, immune disorder, and other factors. These aspects are not technically separated items, but intertwined with each other in the pathogenesis of podocyte injuries.


id: cord-010329-rcx450b6
author: Khazak, Vladimir
date: 2005
txt: ./txt/cord-010329-rcx450b6.txt
cache: ./cache/cord-010329-rcx450b6.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177006/
doi: 10.1007/978-1-59259-948-6_18
summary:
  The methods outlined below describe (1) the construction of expression plasmids bearing conditionally regulated yeast HXT9 and HXT11 hexose transporter genes, (2) integration of HXT9-and HXT11-containing DNA fragments in the PDR1 and PDR3 chromosomal loci of yeast two-hybrid strains, (3) analysis of the permeability of newly developed yeast strains with selected known smallmolecule inhibitors, and by screen of a large combinatorial library of compounds, and (4) selection of inhibitors of the interaction between human Ras and Raf-1 by screening the combinatorial library of compounds in the obtained hyperpermeable yeast two-hybrid strain. cerevisiae to small-molecular-weight compounds, the two yeast hexose transporters HXT9 and HXT11 were subcloned under control of the galactose-inducible GAL1 promoter and subsequently integrated by homologous recombination into the genetic loci for PDR1 and PDR3, thereby destroying the coding sequence of these genes. The plasmid pPDR3-HisInt was digested with AatII-SacI and the purified integrative cassette, hisG-URA3-PDR3-Int (see Fig. 2C ) was transformed into parental strains SKY48 and SKY191.

title:
  Development of a Yeast Two-Hybrid Screen for Selection of Human Ras-Raf Protein Interaction Inhibitors

abstract:
  A yeast two-hybrid screening system was developed to screen for small molecules that inhibit the interaction of the Ras and the Raf proteins. Hyperpermeable yeast strains useful for high-throughput screening (HTS) for the two-hybrid system were created. Differential inhibition of the Ras-Raf vs the hsRPB4-hsRPB7 interaction allowed the identification of selective inhibitors.


id: cord-012837-fuwp08qt
author: Lu, Chen-chen
date: 2020-03-17
txt: ./txt/cord-012837-fuwp08qt.txt
cache: ./cache/cord-012837-fuwp08qt.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471476/
doi: 10.1038/s41401-019-0326-5
summary:
  Therefore, we speculated that in the development of diabetes, the gut microbiota was likely to produce excessive SCFAs, especially acetate, which could bind to renal-related signal receptors, thus activating intrarenal RAS and mediating the early pathophysiological processes of DN. The immunofluorescence staining results also showed significantly decreased expression of glomerular podocyte-specific protein WT-1 and nephrin in the DM group compared with that in the control group, which was relatively recovered in the DM + AB group (Fig. 5e-g) , suggesting that unbalanced gut microbiota might be a key factor resulting in injuries to the glomerular filtration membrane in early DN. The Western blot results to evaluate the degree of intrarenal RAS activation showed that compared with the control group, the protein expression of ACE, Ang II, and AT1R in the kidney of the DM group was significantly increased, and antibiotic treatment showed a suppressing effect on these three RAS-activating indicators (Fig. 6d, e) .

title:
  Gut microbiota dysbiosis-induced activation of the intrarenal renin–angiotensin system is involved in kidney injuries in rat diabetic nephropathy

abstract:
  Some studies have shown that gut microbiota along with its metabolites is closely associated with diabetic mellitus (DM). In this study we explored the relationship between gut microbiota and kidney injuries of early diabetic nephropathy (DN) and its underlying mechanisms. Male SD rats were intraperitoneally injected with streptozotocin to induce DM. DM rats were orally administered compound broad-spectrum antibiotics for 8 weeks. After the rats were sacrificed, their blood, urine, feces, and renal tissues were harvested for analyses. We found that compared with the control rats, DM rats had abnormal intestinal microflora, increased plasma acetate levels, increased proteinuria, thickened glomerular basement membrane, and podocyte foot process effacement in the kidneys. Furthermore, the protein levels of angiotensin II, angiotensin-converting enzyme, and angiotensin II type 1 receptor in the kidneys of DM rats were significantly increased. Administration of broad-spectrum antibiotics in DM rats not only completely killed most intestinal microflora, but also significantly lowered the plasma acetate levels, inhibited intrarenal RAS activation, and attenuated kidney damage. Finally, we showed that plasma acetate levels were positively correlated with intrarenal angiotensin II protein expression (r = 0.969, P < 0.001). In conclusion, excessive acetate produced by disturbed gut microbiota might be involved in the kidney injuries of early DN through activating intrarenal RAS.


id: cord-257558-dgnbfzli
author: Diamond, Betty
date: 2020-06-18
txt: ./txt/cord-257558-dgnbfzli.txt
cache: ./cache/cord-257558-dgnbfzli.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32556101/
doi: 10.1084/jem.20201000
summary:
  ACE2 cleaves angiotensin II to produce a small peptide, ang1-7, which binds to a G protein-coupled receptor Mas to induce an anti-inflammatory and anti-apoptotic program and vasodilation (Simões e Silva et al., 2013) . When the viral spike protein binds ACE2, however, another protease termed TACE, or ADAM 17, is activated; this causes ACE2 to be shed from the cell membrane, leading to decreased degradation of angiotensin II and decreased production of ang1-7 (Shah and Catt, 2006) . A model of COVID-19 might be that SARS-CoV-2 infects lung alveolar epithelial cells, the source of surfactant, causing a cytopathic effect. First, COVID-19 patients will have a high level of angiotensin II, perhaps even African Americans, and a low level of ang1-7 due to the diminished activity of ACE2. Right: In a SARS-CoV-2-infected individual, there is an imbalanced RAS, with viral spike protein causing ACE2 shedding, diminished production of ang1-7, and high AT1 with low AT2.

title:
  The renin–angiotensin system: An integrated view of lung disease and coagulopathy in COVID-19 and therapeutic implications

abstract:
  The renin–angiotensin system (RAS) has long been appreciated as a major regulator of blood pressure, but has more recently been recognized as a mechanism for modulating inflammation as well. While there has been concern in COVID-19 patients over the use of drugs that target this system, the RAS has not been explored fully as a druggable target. The abbreviated description of the RAS suggests that its dysregulation may be at the center of COVID-19.


id: cord-259243-1lkzcslx
author: Álvarez-Aragón, Luis Miguel
date: 2020-04-08
txt: ./txt/cord-259243-1lkzcslx.txt
cache: ./cache/cord-259243-1lkzcslx.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1093/cid/ciaa402
doi: 10.1093/cid/ciaa402
abstract: nan
summary:
  title: Inquiring into Benefits of Independent Activation of Non-Classical Renin-Angiotensin System in the Clinical Prognosis and Reduction of COVID-19 mortality We have read with great interest the elegant manuscript by Hanff et al [1] proposing a very interesting association between the classical renin-angiotensin system (RAS) and angiotensinconverting enzyme 2 (ACE2) dysregulation present in cardiovascular disease (CVD) and the high mortality index in patients with CVD and coronavirus disease 2019 (COVID-19). On the one hand, it will decrease the proinflammatory effect of Angiotensin II with its subsequent benefit on decreasing the risk of acute respiratory distress syndrome (ARDS) observed in these patients, and on the other hand, it will increase ACE2 expression and therefore the virulence of SARS-Cov2. In addition, in vitro studies in human renal cells treated with SLGT2 inhibitors have shown an increment in Angiotensin(1-7) due to the independent activation of the non-classical RES, leading to important anti-inflammatory and anti-M a n u s c r i p t fibrotic effects [6, 7] .

title:
  Inquiring into Benefits of Independent Activation of Non-Classical Renin-Angiotensin System in the Clinical Prognosis and Reduction of COVID-19 mortality


id: cord-269289-6uog10j4
title: Electrolyte Disturbances in SARS-CoV-2 Infection
author: Mabillard, Holly
date: 2020-07-22
txt: ./txt/cord-269289-6uog10j4.txt
cache: ./cache/cord-269289-6uog10j4.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33093945/
doi: 10.12688/f1000research.24441.2
summary:
  These include additional respiratory complications (pulmonary fibrosis -reported in 21% of those hospitalised with SARS-CoV-2 9 months post-discharge in one study 3 ) 7 , cardiovascular complications (acute cardiac injury (7% 8 ), cardiomyopathy (1/3 patients 9 ), cardiac tamponade, heart failure, dysrhythmias (17% 8 ) and venous thromboembolic events (20% 10 )) 11 , neurological complications (myopathy, acute stroke (5.7% of those with severe infection 12 ), Guillain-Barre syndrome (0.4% hospitalised patients 11 ) and encephalopathy) 13 , acute liver and/or pancreatic injury (29% and 17% respectively in one cohort) 14 , cytokine storm syndrome, septic shock, DIC, diarrhoea, Kawasaki-like disease 14 and renal complications (acute tubular injury, rhabdomyolysis, proteinuria, secondary focal segmental glomerulosclerosis and possible renin-angiotensinaldosterone system activation) 15 . The study reported that the degree of hypokalaemia correlated with severity of SARS-CoV-2 symptoms and they suggested that hypokalaemia can be difficult to correct as seen in two patients because the renal potassium wasting persists until clinical recovery from the virus.

abstract:
  The global pandemic secondary to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is leading to unprecedented global morbidity and mortality. With a bewildering array of complications, renal involvement in various forms is common, including serum electrolyte derangements. Hypokalaemia secondary to SARS-CoV-2 was common in a reported Chinese cohort. Here we review the emerging evidence on hypokalaemia and SARS-CoV-2 infection, the potential pathophysiological mechanisms based on early clinical and histopathological data and important clinical implications. Mechanisms of hypokalaemia are multifactorial and so the electrolyte disturbance can be difficult to avoid. We provide further support to the theory of renin-angiotensin-aldosterone (RAS) activation, discuss the strengths and weaknesses of implicating RAS involvement and highlight the importance of calculating the transtubular potassium gradient to identify those at risk of hypokalaemia and its complications.


id: cord-272546-zznm13ik
title: Cardiothoracic robotic assisted surgery in times of COVID-19
author: Van den Eynde, Jef
date: 2020-05-08
txt: ./txt/cord-272546-zznm13ik.txt
cache: ./cache/cord-272546-zznm13ik.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1007/s11701-020-01090-7
doi: 10.1007/s11701-020-01090-7
summary:
  At a time when elective surgeries are being suspended and questions are being raised about how the remaining procedures on COVID-19 positive patients can be performed safely, it is important to consider the potential role of robotic assisted surgery within the current pandemic. To date, however, no specific recommendations are available for cardiothoracic robotic assisted surgery in COVID-19 positive patients. Here, we discuss the potential risks, benefits, and preventive measures that need to be taken into account when considering robotic assisted surgery for cardiothoracic indications in patients with confirmed COVID-19. In response to this situation, various surgical societies have already issued their recommendations on adequate patient selection and preparation, as well as measures that can be taken to minimize the spread of viral particles. Provided that the above discussed risks are taken into account and met with these preventive measures, cardiothoracic RAS might on the other hand have various benefits to offer during the current COVID-19 pandemic when compared to conventional open surgery.

abstract:
  The coronavirus disease 2019 (COVID-19) pandemic poses an immense threat to healthcare systems worldwide. At a time when elective surgeries are being suspended and questions are being raised about how the remaining procedures on COVID-19 positive patients can be performed safely, it is important to consider the potential role of robotic assisted surgery within the current pandemic. Recently, several robotic assisted surgery societies have issued their recommendations. To date, however, no specific recommendations are available for cardiothoracic robotic assisted surgery in COVID-19 positive patients. Here, we discuss the potential risks, benefits, and preventive measures that need to be taken into account when considering robotic assisted surgery for cardiothoracic indications in patients with confirmed COVID-19. It is suggested that robotic assisted surgery might have various advantages such as early recovery after surgery, shorter hospital stay, and reduced loss of blood and fluids as well as smaller incisions. However, electrosurgical and ultrasonic devices, as well as CO2 insufflation should be managed with caution to prevent the risk of aerosolization of viral particles.


id: cord-276260-iccaqz8u
title: Does activation of the protective Renin-Angiotensin System have therapeutic potential in COVID-19?
author: Namsolleck, Pawel
date: 2020-08-17
txt: ./txt/cord-276260-iccaqz8u.txt
cache: ./cache/cord-276260-iccaqz8u.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32807075/
doi: 10.1186/s10020-020-00211-0
summary:
  On the other hand, as part of the Protective Arm of RAS, Ang II also stimulates the angiotensin II type 2 receptor (AT 2 R) and this octapeptide can be further cleaved by the carboxypeptidase ACE2 to yield angiotensin-(1-7) (Ang-(1-7)), an agonist of the Mas receptor (MasR). Here we consider therapeutic perspectives of stable and specific AT 2 R and MasR agonists in The balance between the Detrimental and Protective Arm of RAS is in several aspects seriously disturbed in COVID-19, thus causing a potentially lethal disease (Fig. 1) . Abbreviations RAS: Renin angiotensin system; SARS: Severe acute respiratory syndrome; CoV-2: Coronavirus 2; COVID-19: Coronavirus disease 2019; ARDS: Acute respiratory distress syndrome; AT 2 R: Angiotensin II type 2 receptor; MasR: Mas receptor; ARB: Angiotensin II type 1 receptor blocker; ACE: Angiotensin converting enzyme; ACEi: Angiotensin converting enzyme inhibitor; Ang II: Angiotensin II; Ang-(1-7): Angiotensin-(1-7)

abstract:
  Infection of lung cells by the corona virus results in a loss of the balance between, on the one hand, angiotensin II-mediated stimulation of the angiotensin II type 1 receptor and, on the other hand, stimulation of the angiotensin II type 2 receptor and/or the Mas receptor. The unbalanced enhanced stimulation of the angiotensin II type 1 receptor causes inflammation, edema and contributes to the pathogenesis of severe acute respiratory distress syndrome. Here we hypothesize that stable, receptor-specific agonists of the angiotensin II type 2 receptor and of the Mas receptor are molecular medicines to treat COVID-19 patients. These agonists have therapeutic potential in the acute disease but in addition may reduce COVID-19-associated long-term pulmonary dysfunction and overall end-organ damage of this disease.


id: cord-277766-rxmpi61o
author: Guang, Cuie
date: 2012-06-15
txt: ./txt/cord-277766-rxmpi61o.txt
cache: ./cache/cord-277766-rxmpi61o.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S1875213612000952
doi: 10.1016/j.acvd.2012.02.010
summary:
  In a classical RAS, the substrate angiotensinogen (AGT), which is released into the circulation from the liver, is degraded by the enzyme renin that originates in the kidney, generating the inactive angiotensin I (Ang I). The initial drug development of clinical ACE inhibitors was based on the assumption of an active site related to that of carboxypeptidase A but organized to remove a dipeptide rather than a single amino acid from the Cterminus of its substrate. The protective role of XNT against hypertension-induced cardiac fibrosis is associated with activation of ACE2, increases in Ang-(1-7) and inhibition of extracellular signal-regulated kinases [83] . The hemoregulatory peptide N-acetyl-Ser-Asp-Lys-Pro is a natural and specific substrate of the N-terminal active site of human angiotensinconverting enzyme The N-terminal active centre of human angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide Angiotensin-converting enzyme 2 activation protects against hypertension-induced cardiac fibrosis involving extracellular signal-regulated kinases

title:
  Three key proteases – angiotensin-I-converting enzyme (ACE), ACE2 and renin – within and beyond the renin-angiotensin system

abstract:
  The discovery of angiotensin-I-converting enzyme 2 (ACE2) and a (pro)renin receptor has renewed interest in the physiology of the renin-angiotensin system (RAS). Through the ACE2/angiotensin-(1–7)/Mas counter-regulatory axis, ACE2 balances the vasoconstrictive, proliferative, fibrotic and proinflammatory effects of the ACE/angiotensin II/AT1 axis. The (pro)renin receptor system shows an angiotensin-dependent function related to increased generation of angiotensin I, and an angiotensin-independent aspect related to intracellular signalling. Activation of ACE2 and inhibition of ACE and renin have been at the core of the RAS regulation. The aim of this review is to discuss the biochemistry and biological functions of ACE, ACE2 and renin within and beyond the RAS, and thus provide a perspective for future bioactives from natural plant and/or food resources related to the three proteases.


id: cord-280662-gakayv6e
title: Angiotensin-converting enzyme 2 (ACE2): SARS-CoV-2 receptor and RAS modulator
author: Bian, Jingwei
date: 2020-10-13
txt: ./txt/cord-280662-gakayv6e.txt
cache: ./cache/cord-280662-gakayv6e.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.apsb.2020.10.006
doi: 10.1016/j.apsb.2020.10.006
summary:
  Angiotensin-converting enzyme 2 (ACE2) was rapidly identified as the critical functional receptor for SARS-CoV-2. Given that ACE2 functions as both a SARS-CoV-2 receptor and a RAS modulator, the treatment for COVID-19 presents a dilemma of how to limit virus entry but protect ACE2 physiological functions. We propose five novel working modes for functional receptor for SARS-CoV-2 infection and the routes of ACE2-mediated virus entering host cells, as well as its regulatory mechanism. SARS-CoV-2 has been shown to share the same functional receptor, angiotensin-converting enzyme 2 (ACE2), with severe acute respiratory syndrome coronavirus (SARS-CoV) 4, 5 . SARS-CoV S-protein binding facilitates ADAM17-dependent ACE2 shedding and has been shown to induce viral entry into the cell 52 . Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2)

abstract:
  The coronavirus disease 2019 (COVID-19) outbreak is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2) was rapidly identified as the critical functional receptor for SARS-CoV-2. ACE2 is well-known as a counter-regulator of the renin-angiotensin system (RAS) and plays a key role in the cardiovascular system. Given that ACE2 functions as both a SARS-CoV-2 receptor and a RAS modulator, the treatment for COVID-19 presents a dilemma of how to limit virus entry but protect ACE2 physiological functions. Thus, an in-depth summary of the recent progress of ACE2 research and its relationship to the virus is urgently needed to provide possible solution to the dilemma. Here, we summarize the complexity and interplay between the coronavirus, ACE2 and RAS (including anti-RAS drugs). We propose five novel working modes for functional receptor for SARS-CoV-2 infection and the routes of ACE2-mediated virus entering host cells, as well as its regulatory mechanism. For the controversy of anti-RAS drugs application, we also give theoretical analysis and discussed for drug application. These will contribute to a deeper understanding of the complex mechanisms of underlying the relationship between the virus and ACE2, and provide guidance for virus intervention strategies.


id: cord-289905-dvl2pud2
title: COVID-19 as a Viral Functional ACE2 Deficiency Disorder with ACE2 Related Multi-organ Disease
author: Gan, Rosemary
date: 2020-06-23
txt: ./txt/cord-289905-dvl2pud2.txt
cache: ./cache/cord-289905-dvl2pud2.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.mehy.2020.110024
doi: 10.1016/j.mehy.2020.110024
summary:
  Appreciating the clear differences between SARS and COVID-19 in presentation, poor prognostic indicators related to individuals'' co-morbid status, and biochemical and radiologic profiles, a novel disease model may assist in: 1) the early recognition of atypical (non-respiratory) presentations of disease; 2) early prophylactic treatment intervention for individuals at risk of severe and critical disease which could take place 6 in the community; 3) revised management of pulmonary complications including those related to prone posturing and ventilation protocols; 4) allowing better utilisation of data collated at a global level in the absence of an evidence-based disease model at this time; 5) identification of different markers of disease progression in at-risk individuals. An upregulation of ACE2 expressing cells related to chronic ATII elevation [18] or treatment with ACEinhibitors [19] , may increase the infective potential of SARS-CoV-2 in this group as a consequence of the duality of ACE2 functioning as both a receptor for viral entry to cells and as an enzyme.

abstract:
  SARS-CoV-2, the agent of COVID-19, shares a lineage with SARS-CoV-1, and a common fatal pulmonary profile but with striking differences in presentation, clinical course, and response to treatment. In contrast to SARS-CoV-1 (SARS), COVID-19 has presented as an often bi-phasic, multi-organ pathology, with a proclivity for severe disease in the elderly and those with hypertension, diabetes and cardiovascular disease. Whilst death is usually related to respiratory collapse, autopsy reveals multi-organ pathology. Chronic pulmonary disease is underrepresented in the group with severe COVID-19. A commonality of aberrant renin angiotensin system (RAS) is suggested in the at-risk group. The identification of angiotensin-converting-enzyme 2 (ACE2) as the receptor allowing viral entry to cells precipitated our interest in the role of ACE2 in COVID-19 pathogenesis. We propose that COVID-19 is a viral multisystem disease, with dominant vascular pathology, mediated by global reduction in ACE2 function, pronounced in disease conditions with RAS bias toward angiotensin-converting-enzyme (ACE) over ACE2. It is further complicated by organ specific pathology related to loss of ACE2 expressing cells particularly affecting the endothelium, alveolus, glomerulus and cardiac microvasculature. The possible upregulation in ACE2 receptor expression may predispose individuals with aberrant RAS status to higher viral load on infection and relatively more cell loss. Relative ACE2 deficiency leads to enhanced and protracted tissue, and vessel exposure to angiotensin II, characterised by vasoconstriction, enhanced thrombosis, cell proliferation and recruitment, increased tissue permeability, and cytokine production (including IL-6) resulting in inflammation. Additionally, there is a profound loss of the “protective” angiotensin (1-7), a vasodilator with anti-inflammatory, anti-thrombotic, antiproliferative, antifibrotic, anti-arrhythmic, and antioxidant activity. Our model predicts global vascular insult related to direct endothelial cell damage, vasoconstriction and thrombosis with a disease specific cytokine profile related to angiotensin II rather than “cytokine storm”. Our proposed mechanism of lung injury provides an explanation for early hypoxia without reduction in lung compliance and suggests a need for revision of treatment protocols to address vasoconstriction, thromboprophylaxis, and to minimize additional small airways and alveolar trauma via ventilation choice. Our model predicts long term sequelae of scarring/fibrosis in vessels, lungs, renal and cardiac tissue with protracted illness in at-risk individuals. It is hoped that our model stimulates review of current diagnostic and therapeutic intervention protocols, particularly with respect to early anticoagulation, vasodilatation and revision of ventilatory support choices.


id: cord-298490-p1msabl5
author: Obukhov, Alexander G.
date: 2020-07-15
txt: ./txt/cord-298490-p1msabl5.txt
cache: ./cache/cord-298490-p1msabl5.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.2337/dbi20-0019
doi: 10.2337/dbi20-0019
summary:
  As suggested by the recent reports regarding the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), upon entry into the host, this virus binds to the extracellular domain of ACE2 in nasal, lung, and gut epithelial cells through its spike glycoprotein subunit S1. In this Perspective, we bring attention to specific factors that may complicate COVID-19 in individuals with diabetes including 1) the presence of bone marrow changes (myeloidosis) that predispose those with diabetes to an excessive proinflammatory response (cytokine storm) and contribute to insulin resistance and reduced vascular repair, and worsening function of the heart, kidney, and systemic vasculature as a whole; 2) increased circulating furin levels that could cleave the spike protein and increase infectivity of SARS-CoV-2; 3) dysregulated autophagy that may promote replication and/or reduce viral clearance; and 4) gut dysbiosis that leads to widespread systemic inflammation, increased gut glucose and sodium absorption, and reduced tryptophan and other key amino acid absorption needed for incretin secretion and glucose homeostasis.

title:
  SARS-CoV-2 Infections and ACE2: Clinical Outcomes Linked With Increased Morbidity and Mortality in Individuals With Diabetes

abstract:
  Individuals with diabetes suffering from coronavirus disease 2019 (COVID-19) exhibit increased morbidity and mortality compared with individuals without diabetes. In this Perspective, we critically evaluate and argue that this is due to a dysregulated renin-angiotensin system (RAS). Previously, we have shown that loss of angiotensin-I converting enzyme 2 (ACE2) promotes the ACE/angiotensin-II (Ang-II)/angiotensin type 1 receptor (AT1R) axis, a deleterious arm of RAS, unleashing its detrimental effects in diabetes. As suggested by the recent reports regarding the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), upon entry into the host, this virus binds to the extracellular domain of ACE2 in nasal, lung, and gut epithelial cells through its spike glycoprotein subunit S1. We put forth the hypothesis that during this process, reduced ACE2 could result in clinical deterioration in COVID-19 patients with diabetes via aggravating Ang-II–dependent pathways and partly driving not only lung but also bone marrow and gastrointestinal pathology. In addition to systemic RAS, the pathophysiological response of the local RAS within the intestinal epithelium involves mechanisms distinct from that of RAS in the lung; however, both lung and gut are impacted by diabetes-induced bone marrow dysfunction. Careful targeting of the systemic and tissue RAS may optimize clinical outcomes in subjects with diabetes infected with SARS-CoV-2.


id: cord-303555-mwu72q7w
title: Cell Signaling and Translational Developmental Therapeutics
author: Dent, Paul
date: 2020-10-06
txt: ./txt/cord-303555-mwu72q7w.txt
cache: ./cache/cord-303555-mwu72q7w.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/B9780128204726000025
doi: 10.1016/b978-0-12-820472-6.00002-5
summary:
  Thus, by the mid-to late-1980s a large body of literature existed which argued that signal transduction pathways consisted of a receptor linked to a large GTP-binding protein which in turn regulated an enzyme that generated "second messengers;" the second messengers would then diffuse throughout the cytosol activating cellular processes, predominantly for metabolism. For the EGFR and other subsequently discovered membrane associated tyrosine kinases, e.g. the non-receptor SCR family and the fibroblast growth factor receptor (FGFR) family, understanding how these enzymes signaled into the cell again initially rested on studies using traditional biochemical methods. [71] [72] [73] [74] [75] [76] Contemporaneously with these studies, researchers were determining how receptor tyrosine kinases regulated RAS family small GTP binding proteins, and other groups determining how RAS proteins signaled downstream off the plasma membrane and into the cytosol.

abstract:
  The relationships between drug pharmacodynamics and subsequent changes in cellular signaling processes are complex. Many in vitro cell signaling studies often use drug concentrations above physiologically safe drug levels achievable in a patient's plasma. Drug companies develop agents to inhibit or modify the activities of specific target enzymes, often without a full consideration that their compounds have additional unknown targets. These two negative sequelae, when published together, become impediments against successful developmental therapeutics and translation because this data distorts our understanding of signaling mechanisms and reduces the probability of successfully translating drug-based concepts from the bench to the bedside. This article will discuss cellular signaling in isolation and as it relates to extant single and combined therapeutic drug interventions. This will lead to a hypothetical series standardized sequential approaches describing a rigorous concept to drug development and clinical translation.


id: cord-311099-59pnm4fn
title: Liver disease and the renin–angiotensin system: Recent discoveries and clinical implications
author: Lubel, John S
date: 2008-06-28
txt: ./txt/cord-311099-59pnm4fn.txt
cache: ./cache/cord-311099-59pnm4fn.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/18557800/
doi: 10.1111/j.1440-1746.2008.05461.x
summary:
  Drug therapies targeting the RAS by inhibiting Ang II formation (ACE inhibitors) or binding to its receptor (angiotensin receptor blockers) are now in widespread clinical use and have been shown to reduce tissue injury and fibrosis in cardiac and renal disease independently of their effects on blood pressure. Interestingly, ACE inhibitors and angiotensin receptor blockers increase Ang‐(1–7) production and it has been proposed that some of the beneficial effects of these drugs are mediated through upregulation of Ang‐(1–7) rather than inhibition of Ang II production or receptor binding. 42 A great deal of evidence supporting the role of the RAS in hepatic fibrosis has come from animal studies using ACE inhibitors and angiotensin receptor blockers (ARB). A pilot study examining the effects of 6 months of losartan treatment on liver fibrosis in chronic hepatitis C demonstrated a significant decrease in fibrosis stage in the treated group compared to control patients.

abstract:
  The renin–angiotensin system (RAS) is a key regulator of vascular resistance, sodium and water homeostasis and the response to tissue injury. Historically, angiotensin II (Ang II) was thought to be the primary effector peptide of this system. Ang II is produced predominantly by the effect of angiotensin converting enzyme (ACE) on angiotensin I (Ang I). Ang II acts mainly through the angiotensin II type‐1 receptor (AT(1)) and, together with ACE, these components represent the ‘classical’ axis of the RAS. Drug therapies targeting the RAS by inhibiting Ang II formation (ACE inhibitors) or binding to its receptor (angiotensin receptor blockers) are now in widespread clinical use and have been shown to reduce tissue injury and fibrosis in cardiac and renal disease independently of their effects on blood pressure. In 2000, two groups using different methodologies identified a homolog of ACE, called ACE2, which cleaves Ang II to form the biologically active heptapeptide, Ang‐(1–7). Conceptually, ACE2, Ang‐(1–7), and its putative receptor, the mas receptor represent an ‘alternative’ axis of the RAS capable of opposing the often deleterious actions of Ang II. Interestingly, ACE inhibitors and angiotensin receptor blockers increase Ang‐(1–7) production and it has been proposed that some of the beneficial effects of these drugs are mediated through upregulation of Ang‐(1–7) rather than inhibition of Ang II production or receptor binding. The present review focuses on the novel components and pathways of the RAS with particular reference to their potential contribution towards the pathophysiology of liver disease.


id: cord-313664-qq0h68vc
title: Renin‐angiotensin system revisited
author: Fyhrquist, F.
date: 2008-08-08
txt: ./txt/cord-313664-qq0h68vc.txt
cache: ./cache/cord-313664-qq0h68vc.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/18793332/
doi: 10.1111/j.1365-2796.2008.01981.x
summary:
  The classical RAS as it looked in the middle 1970s consisted of circulating renin, acting on angiotensinogen to produce angiotensin I, which in turn was converted into angiotensin II (Ang II) by angiotensin‐converting enzyme (ACE). The importance of RAS in cardiovascular disease has been demonstrated by the clinical benefits of ACE inhibitors and AT1 receptor blockers. It was not until the discovery of orally effective angiotensin-converting enzyme (ACE) inhibitors, the first of which was captopril [2] , that the paramount importance of RAS in cardiovascular homeostasis and disease was being appreciated. Angiotensin-converting enzyme 2 and Ang 1-7 may play an important role in cardiovascular physiology and pathophysiology, e.g. by modulating or counterbalancing excess activity of the ''classical'' RAS [45, 46] . Angiotensin-converting enzyme inhibitors and ARBs (Fig. 5) are well established corner stones in the prevention and treatment of hypertension and cardiovascular disease, as demonstrated by numerous clinical trials and world wide clinical practice.

abstract:
  New components and functions of the renin‐angiotensin system (RAS) are still being unravelled. The classical RAS as it looked in the middle 1970s consisted of circulating renin, acting on angiotensinogen to produce angiotensin I, which in turn was converted into angiotensin II (Ang II) by angiotensin‐converting enzyme (ACE). Ang II, still considered the main effector of RAS was believed to act only as a circulating hormone via angiotensin receptors, AT1 and AT2. Since then, an expanded view of RAS has gradually emerged. Local tissue RAS systems have been identified in most organs. Recently, evidence for an intracellular RAS has been reported. The new expanded view of RAS therefore covers both endocrine, paracrine and intracrine functions. Other peptides of RAS have been shown to have biological actions; angiotensin 2–8 heptapeptide (Ang III) has actions similar to those of Ang II. Further, the angiotensin 3–8 hexapeptide (Ang IV) exerts its actions via insulin‐regulated amino peptidase receptors. Finally, angiotensin 1–7 (Ang 1–7) acts via mas receptors. The discovery of another ACE2 was an important complement to this picture. The recent discovery of renin receptors has made our view of RAS unexpectedly complex and multilayered. The importance of RAS in cardiovascular disease has been demonstrated by the clinical benefits of ACE inhibitors and AT1 receptor blockers. Great expectations are now generated by the introduction of renin inhibitors. Indeed, RAS regulates much more and diverse physiological functions than previously believed.


id: cord-317423-3nkzp1z2
author: Turk, Can
date: 2020-06-03
txt: ./txt/cord-317423-3nkzp1z2.txt
cache: ./cache/cord-317423-3nkzp1z2.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1177/1470320320928872
doi: 10.1177/1470320320928872
summary:
  RESULTS: The whole-genome expression data of the lung epithelial cells infected with SARS-CoV for 12, 24, and 48 hours were analyzed, and a total of 15 RAS family and 29 immune genes were found to be highly correlated with the exposure time to the virus in the studied groups. 13, 21 The main purpose of this present in silico genomic study was to assess how the expressions of the RAS gene family changes after cellular infection with SARS-CoV in the lung epithelial cell culture. The whole normalized gene expression data of lung epithelial cells infected with SARS-CoV for 12, 24, and 48 hours were compared between different groups in order to determine significantly and differentially expressed RAS family genes. Based on our results, in this phase, as the exposure time to SARS-CoV increases, EGFR and IGF2R, two receptors with key roles in the RAS signaling pathway, were significantly down-regulated in the infected human bronchial epithelial cells.

title:
  In vitro analysis of the renin–angiotensin system and inflammatory gene transcripts in human bronchial epithelial cells after infection with severe acute respiratory syndrome coronavirus

abstract:
  INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently identified coronavirus family member that triggers a respiratory disease similar to severe acute respiratory syndrome coronavirus (SARS-CoV). SARS-CoV and SARS-CoV-2 are very similar to each other in many respects, such as structure, genetics, and pathobiology. We hypothesized that coronaviruses could affect pulmonary tissues via integration with the critical immune genes after their interaction with renin–angiotensin system (RAS) elements. The aim of the present bioinformatics study was to assess expression changes of the RAS and non-RAS genes, particularly immune response genes, in the lung epithelial cells after infection with SARS-CoV. METHODS: Linear regression, hierarchical clustering, pathway analysis, and network analysis were performed using the E-GEOD-17400 data set. RESULTS: The whole-genome expression data of the lung epithelial cells infected with SARS-CoV for 12, 24, and 48 hours were analyzed, and a total of 15 RAS family and 29 immune genes were found to be highly correlated with the exposure time to the virus in the studied groups. CONCLUSION: RAS genes are important at the initiation of the infections caused by coronavirus family members and may have a strong relationship with the exchange of immune genes in due course following the infection.


id: cord-317878-bqpj0ey0
author: Czick, Maureen
date: 2020-09-11
txt: ./txt/cord-317878-bqpj0ey0.txt
cache: ./cache/cord-317878-bqpj0ey0.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.2147/dmso.s265518
doi: 10.2147/dmso.s265518
summary:
  Silent hypoxia, atypical acute respiratory distress syndrome (ARDS), stroke, olfactory loss, myocarditis, and increased mortality rates in the elderly, in men, in African-Americans, and in patients with obesity, diabetes, and cancer—all bear the fingerprints of the renin-angiotensin system (RAS) imbalance, suggesting that RAS is the common culprit. Subpopulations manifesting higher rates of COVID-19 mortality-including hypertensives, the elderly, the obese, diabetics, men, and African-Americans-correlate with preexisting RAS imbalance, with ACE overactivity and/or ACE2 underactivity priming these patients for more severe COVID-19 outcomes. 159 Males generally have higher levels of RAS than premenopausal females, 160 perhaps explaining why male hypertensive rats show a greater blood pressure decrease with ACEIs. 161 Estrogen downregulates the expression of the AT1 gene 162, 163 and suppresses both ROS production in vascular smooth muscle and the enzymatic activity of ACE.

title:
  COVID’s Razor: RAS Imbalance, the Common Denominator Across Disparate, Unexpected Aspects of COVID-19

abstract:
  A modern iteration of Occam’s Razor posits that “the simplest explanation is usually correct.” Coronavirus Disease 2019 involves widespread organ damage and uneven mortality demographics, deemed unexpected from what was originally thought to be “a straightforward respiratory virus.” The simplest explanation is that both the expected and unexpected aspects of COVID-19 share a common mechanism. Silent hypoxia, atypical acute respiratory distress syndrome (ARDS), stroke, olfactory loss, myocarditis, and increased mortality rates in the elderly, in men, in African-Americans, and in patients with obesity, diabetes, and cancer—all bear the fingerprints of the renin-angiotensin system (RAS) imbalance, suggesting that RAS is the common culprit. This article examines what RAS is and how it works, then from that baseline, the article presents the evidence suggesting RAS involvement in the disparate manifestations of COVID-19. Understanding the deeper workings of RAS helps one make sense of severe COVID-19. In addition, recognizing the role of RAS imbalance suggests potential routes to mitigate COVID-19 severity.


id: cord-318327-9sh2eksm
author: Garg, M.
date: 2012-01-05
txt: ./txt/cord-318327-9sh2eksm.txt
cache: ./cache/cord-318327-9sh2eksm.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/22221317/
doi: 10.1111/j.1365-2036.2011.04971.x
summary:
  Animal studies investigating the effects of RAS blockade in a range of conditions including inflammatory bowel disease, functional gut disorders, gastrointestinal malignancy and even intestinal ischaemia have been encouraging to date. Animal studies investigating the effects of RAS blockade in a range of conditions including inflammatory bowel disease, functional gut disorders, gastrointestinal malignancy and even intestinal ischaemia have been encouraging to date. The contemporary view of the RAS has evolved from that of a simple linear pathway involving the conversion of angiotensinogen to angiotensin II (Ang II) via a two-step process facilitated by renin and angiotensin converting enzyme (ACE), to a much more complex system involving homologues of ACE and multiple angiotensin peptides which play supplementary and counter-regulatory roles ( Figure 1 ). Angiotensin converting enzyme inhibition or angiotensin receptor antagonism have been shown to produce a number of beneficial anti-inflammatory effects in rodent models of intestinal inflammation.

title:
  Review article: the pathophysiological roles of the renin–angiotensin system in the gastrointestinal tract

abstract:
  BACKGROUND: The renin‐angiotensin system (RAS) is a homeostatic pathway widely known to regulate cardiovascular and renal physiology; however, little is known about its influence in gastrointestinal tissues. AIM: To elicit the anatomical distribution and physiological significance of the components of the RAS in the gastrointestinal tract. METHODS: An extensive online literature review including Pubmed and Medline. RESULTS: There is evidence for RAS involvement in gastrointestinal physiology and pathophysiology, with all the components required for autonomous regulation identified throughout the gastrointestinal tract. The RAS is implicated in the regulation of glucose, amino acid, fluid and electrolyte absorption and secretion, motility, inflammation, blood flow and possibly malignant disease within the gastrointestinal tract. Animal studies investigating the effects of RAS blockade in a range of conditions including inflammatory bowel disease, functional gut disorders, gastrointestinal malignancy and even intestinal ischaemia have been encouraging to date. Given the ready availability of drugs that modify the RAS and their excellent safety profile, an opportunity exists for investigation of their possible therapeutic role in a variety of human gastrointestinal diseases. CONCLUSIONS: The gastrointestinal renin‐angiotensin system appears to be intricately involved in a number of physiological processes, and provides a possible target for novel investigative and therapeutic approaches.


id: cord-322966-o65fo853
author: Arnold, Ruth H.
date: 2020-05-25
txt: ./txt/cord-322966-o65fo853.txt
cache: ./cache/cord-322966-o65fo853.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S1443950620301451
doi: 10.1016/j.hlc.2020.05.004
summary:
  title: COVID-19 – Does This Disease Kill Due to Imbalance of the Renin Angiotensin System (RAS) Caused by Genetic and Gender Differences in the Response to Viral ACE 2 Attacks? ABSTRACT Debate continues in the medical literature on the role of the renin angiotensin system (RAS) in Coronavirus disease 2019 (COVID-19) pathophysiology and the implications for the use of cardiovascular drugs acting on the RAS. Debate continues in the medical literature on the role of the renin angiotensin system (RAS) in Coronavirus disease 2019 (COVID19) pathophysiology and the implications for the use of cardiovascular drugs acting on the RAS. Debate has arisen due to the finding that underlying cardiovascular disease and hypertension are associated with significantly increased risk of hospitalisation and death in COVID-19 [1, 2] , in addition to the viral receptor being angiotensin-converting enzyme-2 (ACE-2) [3 -5] . Association of renin-angiotensin system inhibitorswith severity or risk of death in patients with hypertension hospitalised for coronavirus disease 19 (COVID-19) infection in Wuhan, China

title:
  COVID-19 – Does This Disease Kill Due to Imbalance of the Renin Angiotensin System (RAS) Caused by Genetic and Gender Differences in the Response to Viral ACE 2 Attacks?

abstract:
  ABSTRACT Debate continues in the medical literature on the role of the renin angiotensin system (RAS) in Coronavirus disease 2019 (COVID-19) pathophysiology and the implications for the use of cardiovascular drugs acting on the RAS. Could these drugs – which include angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptors blockers (ARBs) – be harmful or potential key therapeutic agents in COVID-19?


id: cord-324364-9p04oeac
author: Hasan, Syed Shahzad
date: 2020-09-12
txt: ./txt/cord-324364-9p04oeac.txt
cache: ./cache/cord-324364-9p04oeac.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32918209/
doi: 10.1007/s40256-020-00439-5
summary:
  Original, observational (prospective or retrospective) studies Included patients with coronavirus disease 2019 (COVID19) Documented use of either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) Reported frequency, percentage, and/or adjusted estimate of mortality or disease severity and/or adverse clinical outcomes (septic shock, admission to intensive care units) associated with COVID-19 From any region or language The reported odds ratios (ORs) and hazard ratios (HRs) that had been adjusted for potential covariates in the respective original studies and the corresponding 95% confidence intervals (CIs) were extracted and pooled in a random-effects model to estimate the association between the use of ACEIs/ ARBs and the risk of mortality and severe/critical illness in COVID-19 patients. In fact, the other studies [52, 78, 80, 84] included in the subgroup pooled analysis reported no difference in the risk of severe/ critical illness with the use of ACEIs compared to non-use of the ACEIs. A key strength of this systematic review and meta-analysis was the pooling of adjusted estimates on the mortality and severe/critical outcomes from the use of RAS inhibitors in COVID-19 patients.

title:
  Mortality and Disease Severity Among COVID-19 Patients Receiving Renin-Angiotensin System Inhibitors: A Systematic Review and Meta-analysis

abstract:
  INTRODUCTION: The use of renin-angiotensin system (RAS) inhibitors, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), was alleged to cause a more severe course of novel coronavirus disease 2019 (COVID-19). METHODS: We systematically reviewed the published studies to assess the association of RAS inhibitors with mortality as well as disease severity in COVID-19 patients. A systematic literature search was performed to retrieve relevant original studies investigating mortality and severity (severe/critical disease) in COVID-19 patients with and without exposure to RAS inhibitors. RESULTS: A total of 59 original studies were included for qualitative synthesis. Twenty-four studies that reported adjusted effect sizes (24 studies reported mortality outcomes and 16 studies reported disease severity outcomes), conducted in RAS inhibitor–exposed and unexposed groups, were pooled in random-effects models to estimate overall risk. Quality assessment of studies revealed that most of the studies included were of fair quality. The use of an ACEI/ARB in COVID-19 patients was significantly associated with lower odds (odds ratio [OR] = 0.73, 95% confidence interval [CI] 0.56–0.95; n = 18,749) or hazard (hazard ratio [HR] = 0.75, 95% CI 0.60–0.95; n = 26,598) of mortality compared with non-use of ACEI/ARB. However, the use of an ACEI/ARB was non-significantly associated with lower odds (OR = 0.91, 95% CI 0.75–1.10; n = 7446) or hazard (HR = 0.73, 95% CI 0.33–1.66; n = 6325) of developing severe/critical disease compared with non-use of an ACEI/ARB. DISCUSSION: Since there was no increased risk of harm, the use of RAS inhibitors for hypertension and other established clinical indications can be maintained in COVID-19 patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40256-020-00439-5) contains supplementary material, which is available to authorized users.


id: cord-326498-8oa5gkrp
author: Gemmati, Donato
date: 2020-05-14
txt: ./txt/cord-326498-8oa5gkrp.txt
cache: ./cache/cord-326498-8oa5gkrp.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3390/ijms21103474
doi: 10.3390/ijms21103474
summary:
  Firstly, SARS-CoV-2 has a strong interaction with the human ACE2 receptor, which plays an essential role in cell entry together with transmembrane serine protease 2 (TMPRSS2); it is interesting to note that the ACE2 gene lays on the X-chromosome, thus allowing females to be potentially heterozygous and differently assorted compared to men who are definitely hemizygous. Therefore, proper ACE2 functionality is essential for both virus cell entry and local pulmonary homeostasis, and although it has been previously described that polymorphisms in the ACE2 gene do not affect the outcome of SARS [43] , females might have a higher degree of heterodimer assembling than males, which in turn might show different affinity for the SARS-CoV-2 spike receptor. Therefore, proper ACE2 functionality is essential for both virus cell entry and local pulmonary homeostasis, and although it has been previously described that polymorphisms in the ACE2 gene do not affect the outcome of SARS [43] , females might have a higher degree of heterodimer assembling than males, which in turn might show different affinity for the SARS-CoV-2 spike receptor.

title:
  COVID-19 and Individual Genetic Susceptibility/Receptivity: Role of ACE1/ACE2 Genes, Immunity, Inflammation and Coagulation. Might the Double X-Chromosome in Females Be Protective against SARS-CoV-2 Compared to the Single X-Chromosome in Males?

abstract:
  In December 2019, a novel severe acute respiratory syndrome (SARS) from a new coronavirus (SARS-CoV-2) was recognized in the city of Wuhan, China. Rapidly, it became an epidemic in China and has now spread throughout the world reaching pandemic proportions. High mortality rates characterize SARS-CoV-2 disease (COVID-19), which mainly affects the elderly, causing unrestrained cytokines-storm and subsequent pulmonary shutdown, also suspected micro thromboembolism events. At the present time, no specific and dedicated treatments, nor approved vaccines, are available, though very promising data come from the use of anti-inflammatory, anti-malaria, and anti-coagulant drugs. In addition, it seems that males are more susceptible to SARS-CoV-2 than females, with males 65% more likely to die from the infection than females. Data from the World Health Organization (WHO) and Chinese scientists show that of all cases about 1.7% of women who contract the virus will die compared with 2.8% of men, and data from Hong Kong hospitals state that 32% of male and 15% of female COVID-19 patients required intensive care or died. On the other hand, the long-term fallout of coronavirus may be worse for women than for men due to social and psychosocial reasons. Regardless of sex- or gender-biased data obtained from WHO and those gathered from sometimes controversial scientific journals, some central points should be considered. Firstly, SARS-CoV-2 has a strong interaction with the human ACE2 receptor, which plays an essential role in cell entry together with transmembrane serine protease 2 (TMPRSS2); it is interesting to note that the ACE2 gene lays on the X-chromosome, thus allowing females to be potentially heterozygous and differently assorted compared to men who are definitely hemizygous. Secondly, the higher ACE2 expression rate in females, though controversial, might ascribe them the worst prognosis, in contrast with worldwide epidemiological data. Finally, several genes involved in inflammation are located on the X-chromosome, which also contains high number of immune-related genes responsible for innate and adaptive immune responses to infection. Other genes, out from the RAS-pathway, might directly or indirectly impact on the ACE1/ACE2 balance by influencing its main actors (e.g., ABO locus, SRY, SOX3, ADAM17). Unexpectedly, the higher levels of ACE2 or ACE1/ACE2 rebalancing might improve the outcome of COVID-19 in both sexes by reducing inflammation, thrombosis, and death. Moreover, X-heterozygous females might also activate a mosaic advantage and show more pronounced sex-related differences resulting in a sex dimorphism, further favoring them in counteracting the progression of the SARS-CoV-2 infection.


id: cord-328846-q52fjx99
author: Okuno, Keisuke
date: 2020-09-09
txt: ./txt/cord-328846-q52fjx99.txt
cache: ./cache/cord-328846-q52fjx99.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3390/ijms21186579
doi: 10.3390/ijms21186579
summary:
  Accordingly, in this review article, we discuss potential molecular mechanisms of VSMC senescence such as those induced by AngII and the therapeutic manipulations of senescence to control age-related CVD and associated conditions such as by senolytic. Accordingly, EGFR, mitochondrial fission/Drp1 and ER stress likely play upstream roles in AngII-induced vascular senescence and SASP thus contributing to RAS-mediated pathophysiology in CVDs (Figure 4) . Mitochondrial fission and ER stress likely play upstream roles in AngII-induced vascular senescence and SASP contributing to RAS-mediated pathophysiology in CVDs. In addition to the molecular mechanisms illustrated in Figure 2 , mitochondrial fission and ER stress are enhanced under chronic RAS activation contributing to VSMC senescence [6] . Mitochondrial fission and ER stress likely play upstream roles in AngII-induced vascular senescence and SASP contributing to RAS-mediated pathophysiology in CVDs. In addition to the molecular mechanisms illustrated in Figure 2 , mitochondrial fission and ER stress are enhanced under chronic RAS activation contributing to VSMC senescence [6] .

title:
  Targeting Molecular Mechanism of Vascular Smooth Muscle Senescence Induced by Angiotensin II, A Potential Therapy via Senolytics and Senomorphics

abstract:
  Cardiovascular disease (CVD) is a prevalent issue in the global aging population. Premature vascular aging such as elevated arterial stiffness appears to be a major risk factor for CVD. Vascular smooth muscle cells (VSMCs) are one of the essential parts of arterial pathology and prone to stress-induced senescence. The pervasiveness of senescent VSMCs in the vasculature increases with age and can be further expedited by various stressing events such as oxidative stress, mitochondria dysfunction, endoplasmic reticulum stress, and chronic inflammation. Angiotensin II (AngII) can induce many of these responses in VSMCs and is thus considered a key regulator of VSMC senescence associated with CVD. Understanding the precise mechanisms and consequences of senescent cell accumulation may uncover a new generation of therapies including senolytic and senomorphic compounds against CVD. Accordingly, in this review article, we discuss potential molecular mechanisms of VSMC senescence such as those induced by AngII and the therapeutic manipulations of senescence to control age-related CVD and associated conditions such as by senolytic.


id: cord-335076-mmpox655
title: Angiotensin II Peptides
author: Izumi, Yasukatsu
date: 2013-03-01
txt: ./txt/cord-335076-mmpox655.txt
cache: ./cache/cord-335076-mmpox655.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/B978012385095900186X
doi: 10.1016/b978-0-12-385095-9.00186-x
summary:
  Ang II, via the Ang II type 1 receptor, directly causes cellular phenotypic changes and cell growth, regulates the gene expression of various bioactive substances, and activates multiple intracellular signaling cascades in cardiac myocytes and fibroblasts, as well as vascular endothelial and smooth muscle cells. Recently, new factors have been discovered, such as angiotensin-converting enzyme 2, angiotensin-(1-7), and its receptor Mas. This section summarizes the current knowledge about the broad RAS in the pathophysiology of cardiac hypertrophy and remodeling, heart failure, vascular thickening, and atherosclerosis. Ang II infusion stimulated aortic thrombin receptor mRNA expression in rats, which was blocked by either ARB or the heparin-binding chimera of human Cu/Zn superoxide dismutase but not by normalization of blood pressure with hydralazine treatment, suggesting that Ang II increases vascular thrombin receptor by AT 1 R-mediated superoxide production and may be implicated in the pathophysiology of atherosclerosis by thrombin cascade activation.

abstract:
  ABSTRACT Much evidence supports the notion that angiotensin II (Ang II), the central product of the renin–angiotensin system (RAS), may play a central role not only in the etiology of hypertension but also in the pathophysiology of cardiovascular diseases in humans. Ang II, via the Ang II type 1 receptor, directly causes cellular phenotypic changes and cell growth, regulates the gene expression of various bioactive substances, and activates multiple intracellular signaling cascades in cardiac myocytes and fibroblasts, as well as vascular endothelial and smooth muscle cells. Recently, new factors have been discovered, such as angiotensin-converting enzyme 2, angiotensin-(1-7), and its receptor Mas. This section summarizes the current knowledge about the broad RAS in the pathophysiology of cardiac hypertrophy and remodeling, heart failure, vascular thickening, and atherosclerosis.


id: cord-337511-20yaol5r
author: Ryan, Paul MacDaragh
date: 2020-06-11
txt: ./txt/cord-337511-20yaol5r.txt
cache: ./cache/cord-337511-20yaol5r.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1136/openhrt-2020-001302
doi: 10.1136/openhrt-2020-001302
abstract: nan
summary:
  Interestingly, comparative analysis of two successive SARS epidemics in early 2000s showed that increased affinity of the SARS virus for human ACE2 receptor strongly predicted severity of clinical disease suggesting that spike protein conformation is potentially a key determinant of virulence. 15 Interestingly, in several Wuhan cohorts cardiac injury and arrythmia were prominent in high-risk Figure 3 Homeostasis of RAS-ACE2 under normal healthy conditions 10 19 ; perturbation of RAS-ACE2 homeostasis in cardiovascular disease, hypertension and diabetes mellitus 22 27 ; COVID-19 may potentially further upregulate RAS in CVD patients and deplete ACE2 33 ; proposition that rhACE2 replacement therapy improves RAS-ACE2 balance by augmenting ACE2 and decreasing RAS activation. 35 If the same holds true for SARS-CoV-2, then soluble rhACE2 may reduce ongoing SARS-CoV-2 access to membrane-bound ACE2 receptor, alter favourably local AngII/Ang1-7 levels and inhibit deleterious RAS effects on remaining at risk tissues in COVID-19 patients.

title:
  COVID-19 and relative angiotensin-converting enzyme 2 deficiency: role in disease severity and therapeutic response


id: cord-344012-npob20n0
author: Gheblawi, Mahmoud
date: 2020-05-08
txt: ./txt/cord-344012-npob20n0.txt
cache: ./cache/cord-344012-npob20n0.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1161/circresaha.120.317015
doi: 10.1161/circresaha.120.317015
summary:
  ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system, facilitator of amino acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the renin-angiotensin system, together with implications for the coronavirus disease 2019 pandemic and associated cardiovascular diseases. 21, 22 Ongoing global efforts are focused on manipulating the ACE2/Ang 1-7 axis to curtail SARS-CoV-2 infection while affording maximal protective effects against lung and cardiovascular damage in patients with In this review, we summarize the diverse roles of ACE2, highlighting its role as the SARS-CoV-2 receptor and negative regulator of the RAS, and the implications for the COVID-19 pandemic.

title:
  Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2

abstract:
  ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system, facilitator of amino acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. ACE2 is widely expressed, including, in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has recently been identified as the SARS-CoV-2 receptor, the infective agent responsible for coronavirus disease 2019, providing a critical link between immunity, inflammation, ACE2, and cardiovascular disease. Although sharing a close evolutionary relationship with SARS-CoV, the receptor-binding domain of SARS-CoV-2 differs in several key amino acid residues, allowing for stronger binding affinity with the human ACE2 receptor, which may account for the greater pathogenicity of SARS-CoV-2. The loss of ACE2 function following binding by SARS-CoV-2 is driven by endocytosis and activation of proteolytic cleavage and processing. The ACE2 system is a critical protective pathway against heart failure with reduced and preserved ejection fraction including, myocardial infarction and hypertension, and against lung disease and diabetes mellitus. The control of gut dysbiosis and vascular permeability by ACE2 has emerged as an essential mechanism of pulmonary hypertension and diabetic cardiovascular complications. Recombinant ACE2, gene-delivery of Ace2, Ang 1–7 analogs, and Mas receptor agonists enhance ACE2 action and serve as potential therapies for disease conditions associated with an activated renin-angiotensin system. rhACE2 (recombinant human ACE2) has completed clinical trials and efficiently lowered or increased plasma angiotensin II and angiotensin 1-7 levels, respectively. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the renin-angiotensin system, together with implications for the coronavirus disease 2019 pandemic and associated cardiovascular diseases.


id: cord-349445-yh6ndtgm
title: Targeting Neprilysin (NEP) pathways: A potential new hope to defeat COVID-19 ghost
author: Mohammed El Tabaa, Manar
date: 2020-05-27
txt: ./txt/cord-349445-yh6ndtgm.txt
cache: ./cache/cord-349445-yh6ndtgm.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0006295220302914
doi: 10.1016/j.bcp.2020.114057
summary:
  Therefore, researchers suggested that the use of angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs), may show a positive trend towards the severe inflammatory reactions and endothelial dysfunction caused by stimulating the function of ACE/Ang II/AT-1 axis and thereby, towards the bad pulmonary effects associated with the COVID-19 infection [29, 30] . Since IL-6 would inactivate endothelial nitric oxide synthase (eNOS), it could disrupt NO production [90] , decreasing its level and inducing a state of oxidative stress that may lead to Ang II-induced impairment in endothelial responses [91] Postulating impaired endothelium functions as a principal factor in the pathogenesis of heart failure, hypertension and diabetes, it will be expected to classify the patients of such diseases as high risk groups for COVID-19 development [92] [93] [94] . Taken into consideration the numerous harmful effects possibly induced by Ang II during COVID-19 pathogenesis, we found that most novel studies aim to use the anti-hypertensive drugs which act either by inhibiting the ACE activity or by blocking AT1 receptor, suggesting that action may mitigate the disease severity in COVID-19 patients.

abstract:
  COVID-19 is an ongoing viral pandemic disease that is caused by SARS-CoV2, inducing severe pneumonia in humans. However, several classes of repurposed drugs have been recommended, no specific vaccines or effective therapeutic interventions for COVID-19 are developed till now. Viral dependence on ACE-2, as entry receptors, drove the researchers into RAS impact on COVID-19 pathogenesis. Several evidences have pointed at Neprilysin (NEP) as one of pulmonary RAS components. Considering the protective effect of NEP against pulmonary inflammatory reactions and fibrosis, it is suggested to direct the future efforts towards its potential role in COVID-19 pathophysiology. Thus, the review aimed to shed light on the potential beneficial effects of NEP pathways as a novel target for COVID-19 therapy by summarizing its possible molecular mechanisms. Additional experimental and clinical studies explaining more the relationships between NEP and COVID-19 will greatly benefit in designing the future treatment approaches.


id: cord-351875-e4aw7gkd
title: COVID-19 and Renin Angiotensin Blockers: Current Evidence and Recommendations
author: Messerli, Franz H.
date: 2020-04-13
txt: ./txt/cord-351875-e4aw7gkd.txt
cache: ./cache/cord-351875-e4aw7gkd.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1161/circulationaha.120.047022
doi: 10.1161/circulationaha.120.047022
abstract: nan
summary:
  B oth angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have repeatedly, but not consistently, been documented to slow progression of pulmonary complications in vulnerable patients. 1 These seemingly beneficial findings of renin angiotensin system (RAS) blockade on outcomes in pneumonia resurfaced in the recent literature in relation to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease 2019 (COVID-19), infection. Presently, there are no data regarding a favorable effect of RAS blockade on pulmonary outcome in SARS-CoV-2-infected patients. Direct renin inhibitors ACE indicate angiotensin-converting enzyme; ACEI, angiotensin-converting enzyme inhibitor; ALI, acute-lung injury; ARB, angiotensin II receptor blocker; AT1, angiotensin 1; PCR, polymerase chain reaction; RAS, renin-angiotensin system; RSV, respiratory syncytial virus; and SARS-CoV, severe acute respiratory syndromecoronavirus. There is inconsistent evidence to suggest that RAS blockers exert a favorable effect on pulmonary outcome in viral pneumonia, but no data are available specifically for SARS-CoV-2-infected patients.


id: cord-352854-che3iwu3
author: Hart, Kristen C
date: 1997-12-18
txt: ./txt/cord-352854-che3iwu3.txt
cache: ./cache/cord-352854-che3iwu3.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/9050994/
doi: 10.1038/sj.onc.1200908
summary:
  However, when examined in focus formation assays, transformation of NIH3T3 cells were seen with derivatives of ras(61L) containing a mutated E1 targeting sequence that results in plasma membrane localization. These results demonstrate that: (1) activated ras targeted to Golgi membranes is unable to cause transformation; (2) lipid modifications at the C-terminus are not required for the transforming activity of plasma membrane-anchored ras(61L) derivatives, and serve primarily a targeting function; (3) a transmembrane domain can effectively substitute for C-terminal modifications that would normally target ras to the inner surface of the plasma membrane, indicating that ras(61L) does not need to reversibly dissociate from the membrane as might be allowed by the normal lipidation; and (4) in order to function properly, there exists a critical distance that the ras protein must reside from the plasma membrane.

title:
  Derivatives of activated H-ras lacking C-terminal lipid modifications retain transforming ability if targeted to the correct subcellular location

abstract:
  To examine the ability of ras to activate signal transduction pathways in the absence of lipid modifications, fusion proteins were constructed that target ras(WT) or activated ras(61L) to cellular membranes as integral membrane proteins, using the first transmembrane domain of the E1 protein of avian infectious bronchitis virus (IBV), which contains a cis-Golgi targeting signal. Golgi-targeted derivatives of activated ras were completely inactive in transformation assays. However, when examined in focus formation assays, transformation of NIH3T3 cells were seen with derivatives of ras(61L) containing a mutated E1 targeting sequence that results in plasma membrane localization. Removal of the lipid modification sites in and upstream of the CAAX motif did not abrogate the transforming activity of plasma membrane-localized ras(61L) derivatives, indicating that these lipid modifications are not essential for ras activity, as long as the protein is correctly localized to the plasma membrane. Interestingly, the activity of integral membrane versions of ras(61L) was strictly dependent on a minimum distance between the transmembrane domain anchor region and the coding sequence of ras. Derivatives with only a 3-amino acid linker were inactive, while linkers of either 11- or 22-amino acids were sufficient to restore transforming activity. These results demonstrate that: (1) activated ras targeted to Golgi membranes is unable to cause transformation; (2) lipid modifications at the C-terminus are not required for the transforming activity of plasma membrane-anchored ras(61L) derivatives, and serve primarily a targeting function; (3) a transmembrane domain can effectively substitute for C-terminal modifications that would normally target ras to the inner surface of the plasma membrane, indicating that ras(61L) does not need to reversibly dissociate from the membrane as might be allowed by the normal lipidation; and (4) in order to function properly, there exists a critical distance that the ras protein must reside from the plasma membrane.


