{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T09:40:29Z","timestamp":1793094029074,"version":"4.5.0"},"reference-count":193,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,15]],"date-time":"2021-03-15T00:00:00Z","timestamp":1615766400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Evidence has arisen in recent years suggesting that a tissue renin-angiotensin system (tRAS) is involved in the progression of various human diseases. This system contains two regulatory pathways: a pathological pro-inflammatory pathway containing the Angiotensin Converting Enzyme (ACE)\/Angiotensin II (AngII)\/Angiotensin II receptor type 1 (AGTR1) axis and a protective anti-inflammatory pathway involving the Angiotensin II receptor type 2 (AGTR2)\/ACE2\/Ang1\u20137\/MasReceptor axis. Numerous studies reported the positive effects of pathologic tRAS pathway inhibition and protective tRAS pathway stimulation on the treatment of cardiovascular, inflammatory, and autoimmune disease and the progression of neuropathic pain. Cell senescence and aging are known to be related to RAS pathways. Further, this system directly interacts with SARS-CoV 2 and seems to be an important target of interest in the COVID-19 pandemic. This review focuses on the involvement of tRAS in the progression of the mentioned diseases from an interdisciplinary clinical perspective and highlights therapeutic strategies that might be of major clinical importance in the future.<\/jats:p>","DOI":"10.3390\/cells10030650","type":"journal-article","created":{"date-parts":[[2021,3,15]],"date-time":"2021-03-15T11:38:58Z","timestamp":1615808338000},"page":"650","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["The Tissue Renin-Angiotensin System and Its Role in the Pathogenesis of Major Human Diseases: Quo Vadis?"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2298-3696","authenticated-orcid":false,"given":"Babak","family":"Saravi","sequence":"first","affiliation":[{"name":"AO Research Institute Davos, 7270 Davos, Switzerland"},{"name":"Department of Orthopedics and Trauma Surgery, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9754-6389","authenticated-orcid":false,"given":"Zhen","family":"Li","sequence":"additional","affiliation":[{"name":"AO Research Institute Davos, 7270 Davos, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna N.","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology I, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"},{"name":"Department of Medicine III (Interdisciplinary Medical Intensive Care), Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3027-8946","authenticated-orcid":false,"given":"Bonaventura","family":"Schmid","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frauke K.","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Medical Center, Faculty of Medicine, University of Freiburg, 79106, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9552-3653","authenticated-orcid":false,"given":"Sibylle","family":"Grad","sequence":"additional","affiliation":[{"name":"AO Research Institute Davos, 7270 Davos, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0262-1412","authenticated-orcid":false,"given":"Mauro","family":"Alini","sequence":"additional","affiliation":[{"name":"AO Research Institute Davos, 7270 Davos, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7778-2480","authenticated-orcid":false,"given":"Robert Geoffrey","family":"Richards","sequence":"additional","affiliation":[{"name":"AO Research Institute Davos, 7270 Davos, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8801-2385","authenticated-orcid":false,"given":"Hagen","family":"Schmal","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Trauma Surgery, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"},{"name":"Department of Orthopaedic Surgery, University Hospital Odense, Sdr. Boulevard 29, 5000 Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"S\u00fcdkamp","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Trauma Surgery, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0685-1909","authenticated-orcid":false,"given":"Gernot M.","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Trauma Surgery, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1111\/j.1748-1716.1898.tb00272.x","article-title":"Niere und kreislauf","volume":"8","author":"Tigerstedt","year":"1898","journal-title":"Skand. Archiv Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1152\/physrev.00036.2005","article-title":"Physiology of local renin-angiotensin systems","volume":"86","author":"Paul","year":"2006","journal-title":"Physiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6731093","DOI":"10.1155\/2016\/6731093","article-title":"Age-associated changes in the vascular renin-angiotensin system in mice","volume":"2016","author":"Yoon","year":"2016","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1007\/s00109-012-0894-z","article-title":"Emergence and evolution of the renin-angiotensin-aldosterone system","volume":"90","author":"Fournier","year":"2012","journal-title":"J. Mol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Nehme, A., Zouein, F.A., Deris Zayeri, Z., and Zibara, K. (2019). An update on the tissue renin angiotensin system and its role in physiology and pathology. J. Cardiovasc. Dev. Dis., 6.","DOI":"10.3390\/jcdd6020014"},{"key":"ref_6","unstructured":"Unger, T., Steckelings, U.M., and dos Santos, R.S. (2015). The Protective Arm of the Renin Angiotensin: Functional Aspects and Therapeutic Implications, Elsevier."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e3044","DOI":"10.1038\/cddis.2017.439","article-title":"The intracellular angiotensin system buffers deleterious effects of the extracellular paracrine system","volume":"8","author":"Valenzuela","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/S1357-2725(02)00178-4","article-title":"Local renin\u2013angiotensin systems: The unanswered questions","volume":"35","year":"2003","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"219","DOI":"10.3317\/jraas.2001.035","article-title":"Review: Intracellular angiotensin II: From myth to reality?","volume":"2","author":"Filipeanu","year":"2001","journal-title":"J. Renin. Angiotensin. Aldosterone Syst."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"H404","DOI":"10.1152\/ajpheart.00219.2016","article-title":"Intracrine angiotensin II functions originate from noncanonical pathways in the human heart","volume":"311","author":"Ferrario","year":"2016","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_11","first-page":"415","article-title":"International union of pharmacology. XXIII. The angiotensin II receptors","volume":"52","author":"Catt","year":"2000","journal-title":"Pharmacol. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2437","DOI":"10.1046\/j.1523-1755.2000.00427.x","article-title":"Angiotensin Type 2 receptor is expressed in the adult rat kidney and promotes cellular proliferation and apoptosis","volume":"58","author":"Cao","year":"2000","journal-title":"Kidney Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1002\/(SICI)1096-9861(19960923)373:3<322::AID-CNE2>3.0.CO;2-4","article-title":"Distribution of angiotensin ii type-2 receptor (AT2) MRNA expression in the adult rat brain","volume":"373","author":"Lenkei","year":"1996","journal-title":"J. Comp. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1177\/1470320310379065","article-title":"Developmental changes in AT1 and AT2 receptor-protein expression in rats","volume":"11","author":"Yu","year":"2010","journal-title":"J. Renin. Angiotensin. Aldosterone Syst."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"13293","DOI":"10.1038\/s41598-017-13746-w","article-title":"Angiotensin II type 2 receptor (AT2R) as a novel modulator of inflammation in rheumatoid arthritis synovium","volume":"7","author":"Terenzi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1186\/s13287-017-0617-z","article-title":"Ang II-AT2R increases mesenchymal stem cell migration by signaling through the FAK and RhoA\/Cdc42 pathways in vitro","volume":"8","author":"Xu","year":"2017","journal-title":"Stem. Cell Res. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4857","DOI":"10.1074\/jbc.M807610200","article-title":"Angiotensin II type 2 receptor blockade increases bone mass","volume":"284","author":"Izu","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1016\/j.peptides.2005.02.024","article-title":"Coexpression of AT1 and AT2 receptors by human fibroblasts is associated with resistance to angiotensin II","volume":"26","author":"Galindo","year":"2005","journal-title":"Peptides"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.pharmthera.2008.08.009","article-title":"AT2 Receptors: Functional relevance in cardiovascular disease","volume":"120","author":"Jones","year":"2008","journal-title":"Pharmacol. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"115","DOI":"10.22203\/eCM.v040a07","article-title":"The tissue-renin-angiotensin-system of the human intervertebral disc","volume":"40","author":"Li","year":"2020","journal-title":"eCM"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1161\/CIRCRESAHA.120.317015","article-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","volume":"126","author":"Gheblawi","year":"2020","journal-title":"Circ. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1111\/ggi.13927","article-title":"Effect of renin\u2013angiotensin system on senescence","volume":"20","author":"Mogi","year":"2020","journal-title":"Geriatr. Gerontol. Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1007\/s11906-018-0900-0","article-title":"Inflammation as a regulator of the renin-angiotensin system and blood pressure","volume":"20","author":"Satou","year":"2018","journal-title":"Curr. Hypertens Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1002\/emmm.201000080","article-title":"Angiotensin II revisited: New roles in inflammation, immunology and aging","volume":"2","author":"Benigni","year":"2010","journal-title":"EMBO Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/s11481-019-09894-7","article-title":"Activation of the protective arm of the renin angiotensin system in demyelinating disease","volume":"15","author":"Stone","year":"2020","journal-title":"J. Neuroimmune. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.3389\/fimmu.2020.01572","article-title":"Targeting the protective arm of the renin-angiotensin system to reduce systemic lupus erythematosus related pathologies in MRL-Lpr mice","volume":"11","author":"Soto","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s10020-020-00211-0","article-title":"Does activation of the protective renin-angiotensin system have therapeutic potential in COVID-19?","volume":"26","author":"Namsolleck","year":"2020","journal-title":"Mol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"143","DOI":"10.3389\/fcvm.2020.00143","article-title":"Renin-angiotensin system and Coronavirus disease 2019: A narrative review","volume":"7","author":"Mascolo","year":"2020","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1097\/01.hjh.0000173509.45363.dd","article-title":"A Forkhead in the road to longevity: The molecular basis of lifespan becomes clearer","volume":"23","author":"Morris","year":"2005","journal-title":"J. Hypertens."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.cger.2010.08.004","article-title":"The frail renin-angiotensin system","volume":"27","author":"Abadir","year":"2011","journal-title":"Clin. Geriatr. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"R1787","DOI":"10.1152\/ajpregu.2000.279.5.R1787","article-title":"Activity and responsiveness of the renin-angiotensin system in the aging rat","volume":"279","author":"Thompson","year":"2000","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1093\/ndt\/12.6.1093","article-title":"Ageing and the renin-angiotensin system","volume":"12","author":"Anderson","year":"1997","journal-title":"Nephrol. Dialysis Transplantat."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/S0272-6386(12)70344-X","article-title":"Renal responses to acute angiotensin II inhibition and administered angiotensin II in the aging, conscious, chronically catheterized rat","volume":"22","author":"Baylis","year":"1993","journal-title":"Am. J. Kidney Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1161\/01.HYP.0000073843.56046.45","article-title":"Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates","volume":"41","author":"Wang","year":"2003","journal-title":"Hypertension"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2579","DOI":"10.1210\/endo.139.5.6023","article-title":"Cardiac senescence is associated with enhanced expression of angiotensin II receptor subtypes","volume":"139","author":"Heymes","year":"1998","journal-title":"Endocrinology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"237","DOI":"10.2217\/14796678.4.3.237","article-title":"Aging and the brain renin\u2013angiotensin system: Relevance to Age-related decline in cardiac function","volume":"4","author":"Diz","year":"2008","journal-title":"Future Cardiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.arr.2008.12.002","article-title":"Signaling mechanisms of angiotensin II in regulating vascular senescence","volume":"8","author":"Min","year":"2009","journal-title":"Ageing. Res. Rev."},{"key":"ref_38","first-page":"245","article-title":"The renin-angiotensin system and the biology of skeletal muscle: Mechanisms of muscle wasting in chronic disease states","volume":"127","author":"Delafontaine","year":"2016","journal-title":"Trans. Am. Clin. Climatol. Assoc."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1042\/CS20200486","article-title":"ACE2, Angiotensin 1-7 and skeletal muscle: Review in the era of COVID-19","volume":"134","author":"Yamamoto","year":"2020","journal-title":"Clin. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.bbrc.2011.04.122","article-title":"Angiotensin II induced catabolic effect and muscle atrophy are redox dependent","volume":"409","author":"Sukhanov","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"23823","DOI":"10.1074\/jbc.M112.449074","article-title":"Angiotensin II inhibits satellite cell proliferation and prevents skeletal muscle regeneration","volume":"288","author":"Yoshida","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1161\/HYPERTENSIONAHA.111.174839","article-title":"Angiotensin II upregulates protein phosphatase 2C\u03b1 and inhibits AMP-activated protein kinase signaling and energy balance leading to skeletal muscle wasting","volume":"58","author":"Tabony","year":"2011","journal-title":"Hypertension"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1152\/physrev.00061.2017","article-title":"Sarcopenia: Aging-related loss of muscle mass and function","volume":"99","author":"Larsson","year":"2019","journal-title":"Physiol. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1002\/jcsm.12334","article-title":"Angiotensin-converting enzyme 2 deficiency accelerates and angiotensin 1-7 restores age-related muscle weakness in mice","volume":"9","author":"Takeshita","year":"2018","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Gomes-Santos, I.L., Fernandes, T., Couto, G.K., Ferreira-Filho, J.C.A., Salemi, V.M.C., Fernandes, F.B., Casarini, D.E., Brum, P.C., Rossoni, L.V., and de Oliveira, E.M. (2014). Effects of exercise training on circulating and skeletal muscle renin-angiotensin system in chronic heart failure rats. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0098012"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1172\/JCI36703","article-title":"Disruption of the ang II type 1 receptor promotes longevity in mice","volume":"119","author":"Benigni","year":"2009","journal-title":"J. Clin. Invest."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"14453","DOI":"10.1038\/srep14453","article-title":"Angiotensin II receptor blockade promotes repair of skeletal muscle through down-regulation of aging-promoting C1q expression","volume":"5","author":"Yabumoto","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/j.bcp.2009.06.018","article-title":"Long term treatment with ACE inhibitor enalapril decreases body weight gain and increases life span in rats","volume":"78","author":"Santos","year":"2009","journal-title":"Biochem. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1161\/01.HYP.35.4.908","article-title":"Long-term angiotensin II type 1 receptor blockade with fonsartan doubles lifespan of hypertensive rats","volume":"35","author":"Linz","year":"2000","journal-title":"Hypertension"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3164","DOI":"10.1161\/01.CIR.96.9.3164","article-title":"Long-term ACE inhibition doubles lifespan of hypertensive rats","volume":"96","author":"Linz","year":"1997","journal-title":"Circulation"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s11357-016-9948-4","article-title":"Combined statin and angiotensin-converting enzyme (ACE) inhibitor treatment increases the lifespan of long-lived F1 male mice","volume":"38","author":"Spindler","year":"2016","journal-title":"Age"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"H1351","DOI":"10.1152\/ajpheart.00393.2007","article-title":"Protective effect of long-term angiotensin II inhibition","volume":"293","author":"Basso","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1161\/ATVBAHA.108.166991","article-title":"SIRT1, a longevity gene, downregulates angiotensin II type 1 receptor expression in vascular smooth muscle cells","volume":"28","author":"Miyazaki","year":"2008","journal-title":"ATVB"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s00109-013-1111-4","article-title":"Overexpression of SIRT1 in vascular smooth muscle cells attenuates angiotensin II-induced vascular remodeling and hypertension in mice","volume":"92","author":"Gao","year":"2014","journal-title":"J. Mol. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"24","DOI":"10.5483\/BMBRep.2019.52.1.290","article-title":"Sirtuin signaling in cellular senescence and aging","volume":"52","author":"Lee","year":"2019","journal-title":"BMB Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"291","DOI":"10.3904\/kjim.2014.29.3.291","article-title":"The renin-angiotensin system and aging in the kidney","volume":"29","author":"Yoon","year":"2014","journal-title":"Korean J. Intern. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"26675","DOI":"10.18632\/oncotarget.5596","article-title":"Reciprocal regulation between sirtuin-1 and angiotensin-II in the substantia nigra: Implications for aging and neurodegeneration","volume":"6","author":"Beiroa","year":"2015","journal-title":"Oncotarget"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.nbd.2008.03.003","article-title":"Brain angiotensin enhances dopaminergic cell death via microglial activation and NADPH-derived ROS","volume":"31","author":"Rey","year":"2008","journal-title":"Neurobiol. Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.neurobiolaging.2006.02.018","article-title":"Angiotensin type-1-receptor antagonists reduce 6-hydroxydopamine toxicity for dopaminergic neurons","volume":"28","author":"Rey","year":"2007","journal-title":"Neurobiol. Aging."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1750-1326-2-1","article-title":"Angiotensin type 1 receptor antagonist losartan, reduces MPTP-induced degeneration of dopaminergic neurons in substantia nigra","volume":"2","author":"Grammatopoulos","year":"2007","journal-title":"Mol. Neurodegener."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/1742-2094-8-129","article-title":"Generation of reactive oxygen species in 1-Methyl-4-Phenylpyridinium (MPP+) treated dopaminergic neurons occurs as an NADPH oxidase-dependent two-wave cascade","volume":"8","author":"Zawada","year":"2011","journal-title":"J. Neuroinflamm."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"204.e1","DOI":"10.1016\/j.neurobiolaging.2010.08.006","article-title":"Aging-related changes in the nigral angiotensin system enhances proinflammatory and pro-oxidative markers and 6-OHDA-induced dopaminergic degeneration","volume":"33","author":"Valenzuela","year":"2012","journal-title":"Neurobiol. Aging."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1016\/j.neurobiolaging.2014.01.017","article-title":"Aging-related dysregulation of dopamine and angiotensin receptor interaction","volume":"35","author":"Valenzuela","year":"2014","journal-title":"Neurobiol. Aging."},{"key":"ref_64","first-page":"67","article-title":"Brain renin-angiotensin system and dopaminergic cell vulnerability","volume":"8","author":"Valenzuela","year":"2014","journal-title":"Front. Neuroanat."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"158","DOI":"10.3389\/fendo.2013.00158","article-title":"A Role for the brain RAS in Alzheimer\u2019s and Parkinson\u2019s diseases","volume":"4","author":"Wright","year":"2013","journal-title":"Front. Endocrinol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1002\/mds.25614","article-title":"Dopamine-angiotensin interactions in the basal ganglia and their relevance for Parkinson\u2019s disease","volume":"28","author":"Valenzuela","year":"2013","journal-title":"Mov. Disord."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"F812","DOI":"10.1152\/ajprenal.00655.2013","article-title":"Angiotensin 1\u20137 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity","volume":"306","author":"Mori","year":"2014","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1007\/s11357-012-9408-8","article-title":"Variations of the angiotensin II type 1 receptor gene are associated with extreme human longevity","volume":"35","author":"Benigni","year":"2013","journal-title":"Age"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1172\/JCI7451","article-title":"Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway","volume":"104","author":"Nataraj","year":"1999","journal-title":"J. Clin. Invest."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1093\/ndt\/gfg223","article-title":"Angiotensin II, the immune system and renal diseases: Another road for RAS?","volume":"18","author":"Suzuki","year":"2003","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/S1357-2725(02)00271-6","article-title":"Inflammation and angiotensin II","volume":"35","author":"Suzuki","year":"2003","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/0014-5793(94)00531-1","article-title":"Activation of human peripheral monocytes by angiotensin II","volume":"347","author":"Hahn","year":"1994","journal-title":"FEBS Lett."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/cei.12467","article-title":"Angiotensin II in inflammation, immunity and rheumatoid arthritis: Angiotensin II and rheumatoid arthritis","volume":"179","author":"Chang","year":"2015","journal-title":"Clin. Exp. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.atherosclerosis.2010.05.020","article-title":"Angiotensin II induces c-reactive protein expression through ERK1\/2 and JNK signaling in human aortic endothelial cells","volume":"212","author":"Han","year":"2010","journal-title":"Atherosclerosis"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1161\/01.CIR.0000127955.36250.65","article-title":"Angiotensin type 1 receptor blockers induce peroxisome proliferator\u2013activated receptor-\u03b3 activity","volume":"109","author":"Schupp","year":"2004","journal-title":"Circulation"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1038\/sj.bjp.0705785","article-title":"Irbesartan inhibits human T-Lymphocyte activation through downregulation of activator protein-1: Suppression of T-cell activation by irbesartan","volume":"142","author":"Cheng","year":"2004","journal-title":"Br. J. Pharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1161\/HYPERTENSIONAHA.109.147843","article-title":"Direct angiotensin II type 2 receptor stimulation acts anti-inflammatory through epoxyeicosatrienoic acid and inhibition of nuclear factor \u039aB","volume":"55","author":"Rompe","year":"2010","journal-title":"Hypertension"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1097\/01.fjc.0000137160.76616.cc","article-title":"Angiotensin receptor blockade decreases markers of vascular inflammation","volume":"44","author":"Graninger","year":"2004","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"4496","DOI":"10.1210\/jc.2002-021836","article-title":"Angiotensin II receptor blocker valsartan suppresses reactive oxygen species generation in leukocytes, nuclear Factor-\u039aB, in mononuclear cells of normal subjects: Evidence of an antiinflammatory action","volume":"88","author":"Dandona","year":"2003","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1002\/hep.20420","article-title":"Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis","volume":"40","author":"Yokohama","year":"2004","journal-title":"Hepatology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.bbrc.2003.12.105","article-title":"Angiotensin II type 1 receptor blockade attenuates renal fibrogenesis in an immune-mediated nephritic kidney through counter-activation of angiotensin II Type 2 receptor","volume":"314","author":"Okada","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"14109","DOI":"10.1073\/pnas.1612668113","article-title":"Role of the receptor mas in macrophage-mediated inflammation in vivo","volume":"113","author":"Hammer","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.1038\/s41598-017-02570-x","article-title":"Angiotensin (1-7) ameliorates the structural and biochemical alterations of ovariectomy-induced osteoporosis in rats via activation of ACE-2\/Mas receptor axis","volume":"7","author":"Abuohashish","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"203","DOI":"10.22203\/eCM.v040a13","article-title":"The tissue renin-angiotensin system (TRAS) and the impact of its inhibition on inflammation and bone loss in the periodontal tissue","volume":"40","author":"Saravi","year":"2020","journal-title":"Eur. Cell Mater."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"115041","DOI":"10.1016\/j.bone.2019.115041","article-title":"The angiotensin converting enzyme 2\/angiotensin-(1-7)\/mas receptor axis as a key player in alveolar bone remodeling","volume":"128","author":"Santos","year":"2019","journal-title":"Bone"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Saravi, B., Li, Z., Pfannkuche, J., Wystrach, L., Albers, C.E., Grad, S., Alini, M., Richards, R.G., Lang, C., and S\u00fcdkamp, N. (2020). Angiotensin II Type 1 receptor antagonist losartan inhibits TNF-\u03b1 induced inflammation and degeneration processes in human nucleus pulposus cells. Preprints.","DOI":"10.20944\/preprints202011.0456.v1"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.1161\/CIRCULATIONAHA.107.734384","article-title":"Angiotensin-converting enzyme inhibition improves vascular function in rheumatoid arthritis","volume":"117","author":"Flammer","year":"2008","journal-title":"Circulation"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1136\/ard.2007.082917","article-title":"Angiotensin receptor blockers reduce erythrocyte sedimentation rate levels in patients with rheumatoid arthritis","volume":"67","author":"Perry","year":"2008","journal-title":"Ann. Rheum. Dis."},{"key":"ref_89","first-page":"341","article-title":"Enalapril influence on arterial stiffness in rheumatoid arthritis women: A randomized clinical trial","volume":"6","year":"2019","journal-title":"Front. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1161\/01.CIR.103.7.919","article-title":"Effects of ramipril and vitamin E on atherosclerosis: The study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE)","volume":"103","author":"Lonn","year":"2001","journal-title":"Circulation"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1007\/s00392-005-0222-5","article-title":"Influence of the angiotensin converting enzyme inhibitor ramipril on high-sensitivity C-reactive protein (Hs-CRP) in patients with documented atherosclerosis","volume":"94","author":"Mitrovic","year":"2005","journal-title":"Z. Kardiol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2807","DOI":"10.1161\/01.STR.0000147041.00840.59","article-title":"Different effects of antihypertensive regimens based on fosinopril or hydrochlorothiazide with or without lipid lowering by pravastatin on progression of asymptomatic carotid atherosclerosis: Principal results of PHYLLIS\u2014A randomized double-blind trial","volume":"35","author":"Zanchetti","year":"2004","journal-title":"Stroke"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.atherosclerosis.2008.08.042","article-title":"ACE inhibition with perindopril and biomarkers of atherosclerosis and thrombosis: Results from the PERTINENT study","volume":"204","author":"Ceconi","year":"2009","journal-title":"Atherosclerosis"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/j.jacc.2005.09.055","article-title":"The effect of valsartan, captopril, or both on atherosclerotic events after acute myocardial infarction: An analysis of the valsartan in acute myocardial infarction trial (VALIANT)","volume":"47","author":"McMurray","year":"2006","journal-title":"J. Am. Coll Cardiol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/S0735-1097(00)01138-4","article-title":"Irbesartan, an angiotensin type 1 receptor inhibitor, regulates markers of inflammation in patients with premature atherosclerosis","volume":"37","author":"Navalkar","year":"2001","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.atherosclerosis.2004.07.008","article-title":"Angiotensin II type 1 receptor blockers reduce tissue factor activity and plasminogen activator inhibitor type-1 antigen in hypertensive patients: A randomized, double-blind, placebo-controlled study","volume":"177","author":"Koh","year":"2004","journal-title":"Atherosclerosis"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.12659\/MSM.892996","article-title":"Effects of olmesartan on endothelial progenitor cell mobilization and function in carotid atherosclerosis","volume":"21","author":"Gong","year":"2015","journal-title":"Med. Sci. Monit."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1016\/j.jacc.2009.09.062","article-title":"Impact of olmesartan on progression of coronary atherosclerosis","volume":"55","author":"Hirohata","year":"2010","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.atherosclerosis.2011.10.013","article-title":"Four-year clinical outcomes of the OLIVUS-Ex (impact of olmesartan on progression of coronary atherosclerosis: Evaluation by intravascular ultrasound) extension trial","volume":"220","author":"Hirohata","year":"2012","journal-title":"Atherosclerosis"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1177\/1753944707085982","article-title":"MORE study investigators carotid intima-media thickness and plaque volume changes following 2-year angiotensin II-receptor blockade. The multicentre olmesartan atherosclerosis regression evaluation (MORE) study","volume":"1","author":"Stumpe","year":"2007","journal-title":"Ther. Adv. Cardiovasc. Dis."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.ahj.2015.12.021","article-title":"Effect of angiotensin II Type i receptor blockade with valsartan on carotid artery atherosclerosis: A double blind randomized clinical trial comparing valsartan and placebo (EFFERVESCENT)","volume":"174","author":"Ramadan","year":"2016","journal-title":"Am. Heart J."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1016\/S0002-9149(01)02340-2","article-title":"Effects of eprosartan versus hydrochlorothiazide on markers of vascular oxidation and inflammation and blood pressure (renin-angiotensin system antagonists, oxidation, and inflammation)","volume":"89","author":"Rahman","year":"2002","journal-title":"Am. J. Cardiol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/hr.2010.237","article-title":"The effect of losartan and amlodipine on left ventricular diastolic function and atherosclerosis in japanese patients with mild-to-moderate hypertension (J-ELAN) study","volume":"34","author":"Yamamoto","year":"2011","journal-title":"Hypertens. Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1097\/HCR.0000000000000027","article-title":"A Combination of low-dose fluvastatin and valsartan decreases inflammation and oxidative stress in apparently healthy middle-aged males","volume":"34","author":"Lunder","year":"2014","journal-title":"J. Cardiopulm. Rehabil. Prev."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1097\/MEG.0b013e32834ba188","article-title":"Effects of losartan and amlodipine alone or combined with simvastatin in hypertensive patients with nonalcoholic hepatic steatosis","volume":"24","author":"Fogari","year":"2012","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1007\/s00535-011-0449-z","article-title":"Effects of 1-Year administration of olmesartan on portal pressure and TGF-Beta1 in selected patients with cirrhosis: A randomized controlled trial","volume":"46","author":"Hidaka","year":"2011","journal-title":"J. Gastroenterol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s11568-009-9030-8","article-title":"High dose losartan and ACE gene polymorphism in IgA nephritis","volume":"2","author":"Woo","year":"2008","journal-title":"HUGO J."},{"key":"ref_108","first-page":"PI31","article-title":"Randomized, controlled study of the effects of losartan versus enalapril in small doses on proteinuria and tubular injury in primary glomerulonephritis","volume":"11","author":"Tylicki","year":"2005","journal-title":"Med. Sci. Monit."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"303","DOI":"10.2169\/internalmedicine.52.9066","article-title":"Effects of irbesartan on inflammatory cytokine concentrations in patients with chronic glomerulonephritis","volume":"52","author":"Tsuruoka","year":"2013","journal-title":"Intern. Med."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1016\/j.jacc.2017.04.025","article-title":"2017 ACC\/AHA\/HFSA focused update of the 2013 ACCF\/AHA guideline for the management of heart failure: A report of the American College of Cardiology\/American Heart Association task force on clinical practice guidelines and the heart failure society of America","volume":"70","author":"Yancy","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1093\/eurheartj\/ehw128","article-title":"2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failurethe task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)developed with the special contribution of the Heart Failure Association (HFA) of the ESC","volume":"37","author":"Ponikowski","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.1093\/eurheartj\/ehy339","article-title":"2018 ESC\/ESH guidelines for the management of arterial hypertension","volume":"39","author":"Williams","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1016\/j.jchf.2020.06.020","article-title":"Sacubitril\/valsartan: Neprilysin inhibition 5 years after PARADIGM-HF","volume":"8","author":"Docherty","year":"2020","journal-title":"JACC Heart Fail."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1056\/NEJMoa1409077","article-title":"Angiotensin\u2013neprilysin inhibition versus enalapril in heart failure","volume":"371","author":"McMurray","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"C838","DOI":"10.1152\/ajpcell.1992.263.4.C838","article-title":"Intracardiac detection of angiotensinogen and renin: A localized renin-angiotensin system in neonatal rat heart","volume":"263","author":"Dostal","year":"1992","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/BF02911386","article-title":"Expression of renin and angiotensin-converting enzyme in human hearts","volume":"10","author":"Mochizuki","year":"1995","journal-title":"Heart Vessels"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1161\/01.CIR.86.1.138","article-title":"Expression of the angiotensinogen gene and localization of its protein in the human heart","volume":"86","author":"Sawa","year":"1992","journal-title":"Circulation"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"341","DOI":"10.2310\/6650.2007.00020","article-title":"Intracardiac and intrarenal renin-angiotensin systems: Mechanisms of cardiovascular and renal effects","volume":"55","author":"Raizada","year":"2007","journal-title":"J. Investig. Med."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"3936","DOI":"10.1210\/jcem.87.8.8731","article-title":"Expression of aldosterone synthase gene in failing human heart: Quantitative analysis using modified real-time polymerase chain reaction","volume":"87","author":"Yoshimura","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1161\/01.RES.57.2.312","article-title":"Renin expression by vascular endothelial cells in culture","volume":"57","author":"Lilly","year":"1985","journal-title":"Circ. Res."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1161\/01.RES.87.5.e1","article-title":"A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1\u20139","volume":"87","author":"Donoghue","year":"2000","journal-title":"Circ. Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.mcna.2016.08.017","article-title":"Local renin angiotensin aldosterone systems and cardiovascular diseases","volume":"101","year":"2017","journal-title":"Med. Clin. North Am."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.cardiores.2007.04.007","article-title":"Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice","volume":"75","author":"Oudit","year":"2007","journal-title":"Cardiovasc. Res."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1161\/CIRCHEARTFAILURE.108.840124","article-title":"Loss of angiotensin-converting enzyme 2 accelerates maladaptive left ventricular remodeling in response to myocardial infarction","volume":"2","author":"Kassiri","year":"2009","journal-title":"Circ. Heart Fail."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s10741-019-09837-7","article-title":"Angiotensin II and angiotensin 1\u20137: Which is their role in atrial fibrillation?","volume":"25","author":"Mascolo","year":"2020","journal-title":"Heart Fail Rev."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1177\/1074248412460124","article-title":"Enhanced angiotensin II-induced cardiac and aortic remodeling in ACE2 knockout mice","volume":"18","author":"Alghamri","year":"2013","journal-title":"J. Cardiovasc. Pharmacol. Ther."},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Serneri, G.N.N., Boddi, M., Cecioni, I., Vanni, S., Coppo, M., Papa, M.L., Bandinelli, B., Bertolozzi, I., Polidori, G., and Toscano, T. (2001). Cardiac angiotensin II formation in the clinical course of heart failure and its relationship with left ventricular function. Circ. Res.","DOI":"10.1161\/hh0901.089882"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1161\/HYPERTENSIONAHA.112.191650","article-title":"Cardioprotective effects mediated by angiotensin II type 1 receptor blockade and enhancing angiotensin 1\u20137 in experimental heart failure in angiotensin-converting enzyme 2-null mice","volume":"59","author":"Patel","year":"2012","journal-title":"Hypertension"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1161\/CIRCULATIONAHA.110.955369","article-title":"Angiotensin-converting enzyme 2 suppresses pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction","volume":"122","author":"Zhong","year":"2010","journal-title":"Circulation"},{"key":"ref_130","first-page":"960","article-title":"Jan hypertension","volume":"116","author":"Roks","year":"2015","journal-title":"Circ. Res."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1113\/expphysiol.2012.067165","article-title":"Angiotensin-converting enzyme 2 antagonizes angiotensin II-induced pressor response and NADPH oxidase activation in wistar-kyoto rats and spontaneously hypertensive rats","volume":"98","author":"Lo","year":"2013","journal-title":"Exp. Physiol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.peptides.2014.10.005","article-title":"The role of renin-angiotensin system modulation on treatment and prevention of liver diseases","volume":"62","author":"Feltenberger","year":"2014","journal-title":"Peptides"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1161\/CIRCHEARTFAILURE.113.000672","article-title":"Angiotensin 1\u20137 ameliorates diabetic cardiomyopathy and diastolic dysfunction in db\/db mice by reducing lipotoxicity and inflammation","volume":"7","author":"Mori","year":"2014","journal-title":"Circ. Heart Fail."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1007\/s40262-013-0072-7","article-title":"Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects","volume":"52","author":"Haschke","year":"2013","journal-title":"Clin. Pharmacokinet."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1055\/a-0633-8892","article-title":"Eccentric overload muscle damage is attenuated by a novel angiotensin- (1\u20137) treatment","volume":"39","author":"Becker","year":"2018","journal-title":"Int. J. Sports Med."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s11906-008-0019-9","article-title":"Local adipose tissue renin-angiotensin system","volume":"10","author":"Cassis","year":"2008","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1161\/01.HYP.0000248211.82232.a7","article-title":"Local Renin angiotensin expression regulates human mesenchymal stem cell differentiation to adipocytes","volume":"48","author":"Matsushita","year":"2006","journal-title":"Hypertension"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"E771","DOI":"10.1152\/ajpendo.00560.2005","article-title":"Angiotensin II induces monocyte chemoattractant protein-1 expression via a nuclear factor-kappab-dependent pathway in rat preadipocytes","volume":"291","author":"Tsuchiya","year":"2006","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1038\/sj.ki.5001810","article-title":"Blockade of angiotensin II type-1 receptor reduces oxidative stress in adipose tissue and ameliorates adipocytokine dysregulation","volume":"70","author":"Kurata","year":"2006","journal-title":"Kidney Int."},{"key":"ref_140","first-page":"82","article-title":"A Population-based assessment of chronic unexplained vulvar pain: Have we underestimated the prevalence of vulvodynia?","volume":"58","author":"Harlow","year":"2003","journal-title":"J. Am. Med. Womens Assoc."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/S0029-7844(98)80136-1","article-title":"Biopsychosocial profile of women with dyspareunia","volume":"90","author":"Meana","year":"1997","journal-title":"Obstet. Gynecol."},{"key":"ref_142","first-page":"624","article-title":"Psychosocial and sexual functioning in women with vulvodynia and chronic pelvic pain. A comparative evaluation","volume":"45","author":"Reed","year":"2000","journal-title":"J. Reprod. Med."},{"key":"ref_143","first-page":"47","article-title":"Vulvar vestibulitis syndrome: An exploratory case-control study","volume":"83","author":"Bazin","year":"1994","journal-title":"Obstet. Gynecol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1067\/mob.2002.125889","article-title":"Differential characterization of women with vulvar vestibulitis syndrome","volume":"187","author":"Witkin","year":"2002","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.jpain.2016.12.008","article-title":"A Local inflammatory renin-angiotensin system drives sensory axon sprouting in provoked vestibulodynia","volume":"18","author":"Liao","year":"2017","journal-title":"J. Pain"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1097\/00004347-199801000-00002","article-title":"Histopathologic features of vulvar vestibulitis","volume":"17","author":"Chadha","year":"1998","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1159\/000010045","article-title":"Increased intraepithelial innervation in women with vulvar vestibulitis syndrome","volume":"46","author":"Hilliges","year":"1998","journal-title":"Gynecol. Obstet. Invest."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1046\/j.1365-2133.2003.05308.x","article-title":"Increased innervation of the vulval vestibule in patients with vulvodynia","volume":"148","author":"Tympanidis","year":"2003","journal-title":"Br. J. Dermatol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"31686","DOI":"10.1074\/jbc.274.44.31686","article-title":"Activation of the AT(2) receptor of angiotensin ii induces neurite outgrowth and cell migration in microexplant cultures of the cerebellum","volume":"274","author":"Do","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/S0169-328X(98)00079-5","article-title":"Sciatic nerve transection evokes lasting up-regulation of angiotensin AT2 and AT1 receptor MRNA in adult rat dorsal root ganglia and sciatic nerves","volume":"57","author":"Gallinat","year":"1998","journal-title":"Brain Res. Mol. Brain Res."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1096\/fj.02-1193fje","article-title":"Angiotensin II accelerates functional recovery in the rat sciatic nerve in vivo: Role of the AT2 receptor and the transcription factor NF-KappaB","volume":"17","author":"Reinecke","year":"2003","journal-title":"FASEB J."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s12990-015-0038-x","article-title":"Mechanisms underlying clinical efficacy of angiotensin II Type 2 Receptor (AT2R) antagonist EMA401 in neuropathic pain: Clinical tissue and in vitro studies","volume":"11","author":"Anand","year":"2015","journal-title":"Mol. Pain"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1002\/j.1532-2149.2012.00269.x","article-title":"Angiotensin II type 2 receptor (AT2 R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons","volume":"17","author":"Anand","year":"2013","journal-title":"Eur. J. Pain"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"3452","DOI":"10.1210\/en.2008-0061","article-title":"Estrogen elicits dorsal root ganglion axon sprouting via a renin-angiotensin system","volume":"149","author":"Chakrabarty","year":"2008","journal-title":"Endocrinology"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.jpain.2017.10.006","article-title":"Inflammatory renin-angiotensin system disruption attenuates sensory hyperinnervation and mechanical hypersensitivity in a rat model of provoked vestibulodynia","volume":"19","author":"Chakrabarty","year":"2018","journal-title":"J. Pain"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"178","DOI":"10.2174\/1389450116666150825115658","article-title":"Renin-angiotensin-aldosterone system: A current drug target for the management of neuropathic pain","volume":"17","author":"Muthuraman","year":"2016","journal-title":"Curr. Drug Targets"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1177\/1470320313503694","article-title":"Renin-angiotensin system in pain: Existing in a double life?","volume":"15","author":"Bali","year":"2014","journal-title":"J. Renin. Angiotensin. Aldosterone Syst."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1586\/14737175.2016.1150179","article-title":"The Therapeutic potential of renin angiotensin aldosterone system (RAAS) in chronic pain: From preclinical studies to clinical trials","volume":"16","author":"Bessaguet","year":"2016","journal-title":"Expert Rev. Neurother."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1111\/pme.12063","article-title":"Small molecule angiotensin II type 2 receptor (AT\u2082R) antagonists as novel analgesics for neuropathic pain: Comparative pharmacokinetics, radioligand binding, and efficacy in rats","volume":"14","author":"Smith","year":"2013","journal-title":"Pain Med."},{"key":"ref_160","doi-asserted-by":"crossref","unstructured":"Ingraham, N.E., Barakat, A.G., Reilkoff, R., Bezdicek, T., Schacker, T., Chipman, J.G., Tignanelli, C.J., and Puskarich, M.A. (2020). Understanding the renin-angiotensin-aldosterone-SARS-CoV axis: A comprehensive review. Eur. Respir. J., 56.","DOI":"10.1183\/13993003.00912-2020"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1093\/eurheartj\/ehaa311","article-title":"Cell type-specific expression of the putative SARS-CoV-2 receptor ACE2 in human hearts","volume":"41","author":"Nicin","year":"2020","journal-title":"Eur. Heart J."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1093\/eurheartj\/ehaa373","article-title":"Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors","volume":"41","author":"Sama","year":"2020","journal-title":"Eur. Heart J."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1038\/s41401-020-0430-6","article-title":"Recombinant human ACE2: Potential therapeutics of SARS-CoV-2 infection and its complication","volume":"41","author":"Pang","year":"2020","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1038\/nm1267","article-title":"A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS Coronavirus\u2013induced lung injury","volume":"11","author":"Kuba","year":"2005","journal-title":"Nat. Med."},{"key":"ref_165","doi-asserted-by":"crossref","unstructured":"Pucci, F., Bogaerts, P., and Rooman, M. (2020). Modeling the molecular impact of SARS-CoV-2 infection on the renin-angiotensin system. Viruses, 12.","DOI":"10.3390\/v12121367"},{"key":"ref_166","doi-asserted-by":"crossref","unstructured":"Van Lier, D., Kox, M., Santos, K., van der Hoeven, H., Pillay, J., and Pickkers, P. (2021). Increased blood angiotensin converting enzyme 2 activity in critically Ill COVID-19 patients. ERJ Open Res., 00848\u201302020.","DOI":"10.1183\/23120541.00848-2020"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.ijid.2020.11.184","article-title":"A dramatic rise in serum ACE2 activity in a critically Ill COVID-19 patient","volume":"103","author":"Nagy","year":"2021","journal-title":"Int. J. Infect. Dis."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"e59177","DOI":"10.7554\/eLife.59177","article-title":"A Mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm","volume":"9","author":"Garvin","year":"2020","journal-title":"eLife"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"155151","DOI":"10.1016\/j.cyto.2020.155151","article-title":"COVID-19 cytokine storm: The anger of inflammation","volume":"133","author":"Mahmudpour","year":"2020","journal-title":"Cytokine"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1161\/HYPERTENSIONAHA.120.15353","article-title":"COVID-19: ACE2centric infective disease?","volume":"76","author":"Verdecchia","year":"2020","journal-title":"Hypertension"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/s41440-020-0455-8","article-title":"Interactions of Coronaviruses with ACE2, Angiotensin II, and RAS inhibitors\u2014Lessons from available evidence and insights into COVID-19","volume":"43","author":"Kai","year":"2020","journal-title":"Hypertens. Res."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1007\/s11427-020-1643-8","article-title":"Clinical and biochemical indexes from 2019-NCoV infected patients linked to viral loads and lung injury","volume":"63","author":"Liu","year":"2020","journal-title":"Sci. China Life Sci."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1016\/S2213-2600(20)30418-5","article-title":"Human recombinant soluble ACE2 in severe COVID-19","volume":"8","author":"Zoufaly","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/nature03712","article-title":"Angiotensin-converting enzyme 2 protects from severe acute lung failure","volume":"436","author":"Imai","year":"2005","journal-title":"Nature"},{"key":"ref_175","first-page":"118","article-title":"Angiotensin II type 1 receptor blocker inhibits pulmonary injury","volume":"28","author":"Mancini","year":"2005","journal-title":"Clin. Invest. Med."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"e34","DOI":"10.1161\/HYPERTENSIONAHA.120.15841","article-title":"Plasma angiotensin peptide profiling and ACE (Angiotensin-Converting Enzyme)-2 activity in COVID-19 patients treated with pharmacological blockers of the renin-angiotensin system","volume":"76","author":"Kintscher","year":"2020","journal-title":"Hypertension"},{"key":"ref_177","doi-asserted-by":"crossref","unstructured":"Rieder, M., Wirth, L., Pollmeier, L., Jeserich, M., Goller, I., Baldus, N., Schmid, B., Busch, H.-J., Hofmann, M., and Kern, W. (2020). Serum ACE-2, angiotensin II, and aldosterone levels are unchanged in patients with COVID-19. Am. J. Hypertens.","DOI":"10.1093\/ajh\/hpaa169"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"2001157","DOI":"10.1183\/13993003.01157-2020","article-title":"The liaison between respiratory failure and high blood pressure: Evidence from COVID-19 patients","volume":"56","author":"Vicenzi","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1002\/cpt.1863","article-title":"Risks of ACE inhibitor and ARB usage in COVID-19: Evaluating the evidence","volume":"108","author":"Sriram","year":"2020","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.ahj.2020.05.002","article-title":"Continuing versus suspending angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: Impact on adverse outcomes in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)--the brace Corona trial","volume":"226","author":"Lopes","year":"2020","journal-title":"Am. Heart J."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"L341","DOI":"10.1152\/ajplung.00360.2012","article-title":"Agonists of MAS oncogene and angiotensin II type 2 receptors attenuate cardiopulmonary disease in rats with neonatal hyperoxia-induced lung injury","volume":"305","author":"Wagenaar","year":"2013","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s11906-012-0291-6","article-title":"Impact of the AT(2) receptor agonist C21 on blood pressure and beyond","volume":"14","author":"Foulquier","year":"2012","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_183","doi-asserted-by":"crossref","unstructured":"Hemnes, A.R., Rathinasabapathy, A., Austin, E.A., Brittain, E.L., Carrier, E.J., Chen, X., Fessel, J.P., Fike, C.D., Fong, P., and Fortune, N. (2018). A Potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension. Eur. Respir. J., 51.","DOI":"10.1183\/13993003.02638-2017"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"L269","DOI":"10.1152\/ajplung.00222.2010","article-title":"Regulation of alveolar epithelial cell survival by the ACE-2\/Angiotensin 1\u20137\/Mas Axis","volume":"301","author":"Uhal","year":"2011","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1093\/rheumatology\/keh398","article-title":"The non-thiol angiotensin-converting enzyme inhibitor quinapril suppresses inflammatory arthritis","volume":"44","author":"Dalbeth","year":"2005","journal-title":"Rheumatology"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1248\/bpb.b16-00296","article-title":"Olmesartan prevented intra-articular inflammation induced by zymosan in rats","volume":"39","author":"Guerra","year":"2016","journal-title":"Biol. Pharm. Bull."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1002\/art.21040","article-title":"Angiotensin receptor blockers suppress antigen-specific T cell responses and ameliorate collagen-induced arthritis in mice","volume":"52","author":"Sagawa","year":"2005","journal-title":"Arthritis Rheum."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.ejphar.2012.10.024","article-title":"Evaluation of the effect of losartan and methotrexate combined therapy in adjuvant-induced arthritis in rats","volume":"698","author":"Refaat","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"ref_189","doi-asserted-by":"crossref","unstructured":"Yoshiji, H., Noguchi, R., Ikenaka, Y., Namisaki, T., Kitade, M., Kaji, K., Shirai, Y., Yoshii, J., Yanase, K., and Yamazaki, M. (2009). Losartan, an angiotensin-II type 1 receptor blocker, attenuates the liver fibrosis development of non-alcoholic steatohepatitis in the rat. BMC Res. Notes, 2.","DOI":"10.1186\/1756-0500-2-70"},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.ejphar.2008.04.028","article-title":"Olmesartan ameliorates a dietary rat model of non-alcoholic steatohepatitis through its pleiotropic effects","volume":"588","author":"Kurita","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1111\/j.1478-3231.2009.02006.x","article-title":"Telmisartan attenuates progression of steatohepatitis in mice: Role of hepatic macrophage infiltration and effects on adipose tissue","volume":"29","author":"Kudo","year":"2009","journal-title":"Liver. Int."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s00441-011-1132-7","article-title":"Telmisartan improves nonalcoholic steatohepatitis in medaka (Oryzias Latipes) by reducing macrophage infiltration and fat accumulation","volume":"344","author":"Kuwashiro","year":"2011","journal-title":"Cell Tissue Res."},{"key":"ref_193","doi-asserted-by":"crossref","unstructured":"De Abajo, F.J. (2020). Renin\u2013angiotensin system inhibitors and COVID-19: Overwhelming evidence against an association. Lancet Digit. Health.","DOI":"10.1016\/S2589-7500(20)30294-6"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/3\/650\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:35:52Z","timestamp":1760160952000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/3\/650"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,15]]},"references-count":193,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["cells10030650"],"URL":"https:\/\/doi.org\/10.3390\/cells10030650","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,15]]}}}