{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T01:02:03Z","timestamp":1791075723165,"version":"4.1.0"},"reference-count":41,"publisher":"The Endocrine Society","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,11,1]]},"abstract":"<jats:p>Emerging evidence indicates that pancreatic tissue expresses all components of the renin-angiotensin system. However, the functional role is not well understood. This investigation examined renin inhibition on pancreas structure\/function in the transgenic Ren2 rat harboring the mouse renin gene, a model of tissue renin overexpression. Renin is the rate-limiting step in the generation of angiotensin II (Ang II), which stimulates the generation of reactive oxygen species in a variety of tissues. Overexpression of renin in Ren2 rats results in hypertension, insulin resistance, and cardiovascular and renal damage. Young (6\u20137 wk old) insulin-resistant male Ren2 and age-matched insulin sensitive Sprague Dawley rats were treated with the renin inhibitor, aliskiren (50 mg\/kg\u00b7d by ip injection), or placebo for 21 d. At 21 d, the Ren2 demonstrated insulin resistance with increased islet insulin, Ang II, and reduced total insulin receptor substrate (IRS)-1, IRS-2, and Akt immunostaining. There was increased islet nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and subunits (p47phox and Rac1) as well as increased nitrotyrosine immunostaining (each P &amp;lt; 0.05). These functional abnormalities were associated with a disordered islet architecture; increased islet-exocrine interface, pericapillary fibrosis, and structurally abnormal mitochondria and content in endocrine and exocrine pancreas. In vivo treatment with aliskiren normalized systemic insulin resistance and islet insulin, Ang II, NADPH oxidase activity\/subunits, and nitrotyrosine and improved total IRS-1 and Akt phosphorylation (each P &amp;lt; 0.05) as well as islet\/exocrine structural abnormalities. Collectively, these data suggest that pancreatic functional\/structural changes are driven, in part, by tissue renin-angiotensin system-mediated increases in NADPH oxidase and reactive oxygen species generation, abnormalities attenuated with direct renin inhibition.<\/jats:p>","DOI":"10.1210\/en.2008-0070","type":"journal-article","created":{"date-parts":[[2008,7,25]],"date-time":"2008-07-25T01:10:28Z","timestamp":1216948228000},"page":"5643-5653","source":"Crossref","is-referenced-by-count":62,"title":["Renin Inhibition Attenuates Insulin Resistance, Oxidative Stress, and Pancreatic Remodeling in the Transgenic Ren2 Rat"],"prefix":"10.1210","volume":"149","author":[{"given":"Javad","family":"Habibi","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (J.H., A.W.-C., M.R.H., V.G.D., R.S., S.D.S., P.K., J.R.S.), University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212"},{"name":"Diabetes Cardiovascular Center (J.H., A.W.-C., M.R.H., V.G.D., R.S., J.R.S.), University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Whaley-Connell","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (J.H., A.W.-C., M.R.H., V.G.D., R.S., S.D.S., P.K., J.R.S.), University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212"},{"name":"Nephrology (A.W.-C.), University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212"},{"name":"Diabetes Cardiovascular Center (J.H., A.W.-C., M.R.H., V.G.D., R.S., J.R.S.), University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melvin R.","family":"Hayden","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (J.H., A.W.-C., M.R.H., V.G.D., R.S., S.D.S., P.K., J.R.S.), University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212"},{"name":"Diabetes Cardiovascular Center (J.H., A.W.-C., M.R.H., V.G.D., R.S., J.R.S.), University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent G.","family":"DeMarco","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (J.H., A.W.-C., M.R.H., V.G.D., R.S., S.D.S., P.K., J.R.S.), University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212"},{"name":"Diabetes Cardiovascular Center (J.H., A.W.-C., M.R.H., V.G.D., R.S., J.R.S.), University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Schneider","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (J.H., A.W.-C., M.R.H., V.G.D., R.S., S.D.S., P.K., J.R.S.), University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212"},{"name":"Diabetes Cardiovascular Center (J.H., A.W.-C., M.R.H., V.G.D., R.S., J.R.S.), University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan D.","family":"Sowers","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (J.H., A.W.-C., M.R.H., V.G.D., R.S., S.D.S., P.K., J.R.S.), University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poorna","family":"Karuparthi","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (J.H., A.W.-C., M.R.H., V.G.D., R.S., S.D.S., P.K., J.R.S.), University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos M.","family":"Ferrario","sequence":"first","affiliation":[{"name":"Wake Forest University School of Medicine (C.M.F.), Wake Forest University, Winston-Salem, North Carolina 27157"},{"name":"Harry S. Truman Veterans Affairs Medical Center (A.W.-C., J.R.S.), Columbia, Missouri 65201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James R.","family":"Sowers","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (J.H., A.W.-C., M.R.H., V.G.D., R.S., S.D.S., P.K., J.R.S.), University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212"},{"name":"Physiology and Pharmacology (J.R.S.), University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212"},{"name":"Diabetes Cardiovascular Center (J.H., A.W.-C., M.R.H., V.G.D., R.S., J.R.S.), University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2008,7,24]]},"reference":[{"key":"2020071612344022900_R1","doi-asserted-by":"crossref","first-page":"H2009","DOI":"10.1152\/ajpheart.00522.2007","article-title":"Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance","volume":"293","author":"Cooper,","year":"2007","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2020071612344022900_R2","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1007\/s00125-003-1295-1","article-title":"Evidence for a local angiotensin system and dose-dependent inhibition of glucose-stimulated insulin release by angiotensin II in isolated pancreatic islets.","volume":"47","author":"Lau","year":"2004","journal-title":"Diabetologia"},{"key":"2020071612344022900_R3","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1677\/joe.0.1610317","article-title":"The tissue renin-angiotensin system in human pancreas.","volume":"161","author":"Tahmasebi","year":"1999","journal-title":"J Endocrinol"},{"key":"2020071612344022900_R4","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1677\/jme.0.0260155","article-title":"Tissue renin-angiotensin system: its expression, localization, regulation and potential role in the pancreas.","volume":"26","author":"Leung","year":"2001","journal-title":"J Mol Endocrinol"},{"key":"2020071612344022900_R5","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1016\/S1357-2725(02)00179-6","article-title":"A local pancreatic renin-angiotensin system: endocrine and exocrine roles.","volume":"35","author":"Leung","year":"2003","journal-title":"Int J Biochem Cell Biol"},{"key":"2020071612344022900_R6","doi-asserted-by":"crossref","first-page":"989","DOI":"10.2337\/diabetes.53.4.989","article-title":"Improved islet morphology after blockade of the renin-angiotensin system in the ZDF rat.","volume":"53","author":"Tikellis","year":"2004","journal-title":"Diabetes"},{"key":"2020071612344022900_R7","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.bbrc.2005.05.065","article-title":"Increased expression of NAD(P)H oxidase in islets of animal models of type 2 diabetes and its improvement by AT1 receptor antagonist.","volume":"332","author":"Nakayama","year":"2005","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071612344022900_R8","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.2337\/diabetes.52.6.1457","article-title":"Pancreatic \u03b2-cells express phagocyte-like NAD(P)H oxidase.","volume":"52","author":"Oliveira","year":"2003","journal-title":"Diabetes"},{"key":"2020071612344022900_R9","doi-asserted-by":"crossref","first-page":"E353","DOI":"10.1152\/ajpendo.00402.2004","article-title":"Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression","volume":"288","author":"Blendea","year":"2005","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2020071612344022900_R10","doi-asserted-by":"crossref","first-page":"F1308","DOI":"10.1152\/ajprenal.00167.2006","article-title":"Oxidative stress and glomerular filtration barrier injury: role of the renin-angiotensin system in the Ren2 transgenic rat","volume":"291","author":"Whaley-Connell","year":"2006","journal-title":"Am J Physiol Renal Physiol"},{"key":"2020071612344022900_R11","doi-asserted-by":"crossref","first-page":"35137","DOI":"10.1074\/jbc.M601320200","article-title":"Angiotensin II-induced NADPH oxidase activation impairs insulin signaling in skeletal muscle cells.","volume":"281","author":"Wei","year":"2006","journal-title":"J Biol Chem"},{"key":"2020071612344022900_R12","doi-asserted-by":"crossref","first-page":"E355","DOI":"10.1152\/ajpendo.00632.2006","article-title":"Angiotensin-II mediated oxidative stress promotes myocardial tissue remodeling in the transgenic TG (mRen2) 27 Ren2 Rat","volume":"293","author":"Whaley-Connell","year":"2007","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2020071612344022900_R13","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1210\/en.2006-1355","article-title":"Rosuvastatin, a HMG-CoA reductase inhibitor, decreases cardiac oxidative stress and remodeling in Ren2 transgenic rats.","volume":"148","author":"Habibi","year":"2007","journal-title":"Endocrinology"},{"key":"2020071612344022900_R14","doi-asserted-by":"crossref","first-page":"3773","DOI":"10.1210\/en.2006-1691","article-title":"Mineralocorticoid receptor blockade attenuates chronic angiotensin-II overexpression stimulation of NADPH oxidase and cardiac remodeling.","volume":"148","author":"Stas","year":"2007","journal-title":"Endocrinology"},{"key":"2020071612344022900_R15","doi-asserted-by":"crossref","first-page":"F861","DOI":"10.1152\/ajprenal.00252.2006","article-title":"Proximal tubule microvilli remodeling and albuminuria in the Ren2 transgenic rat","volume":"292","author":"Hayden","year":"2007","journal-title":"Am J Physiol Renal Physiol"},{"key":"2020071612344022900_R16","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1111\/j.0197-3118.2006.05454.x","article-title":"Organ involvement in cardiometabolic syndrome.","volume":"1","author":"Hayden","year":"2006","journal-title":"J Cardiometab Syndr"},{"key":"2020071612344022900_R17","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1089\/ars.2007.1610","article-title":"Isletopathy in type 2 diabetes: implications of islet RAS, islet fibrosis, islet amyloid, remodeling, and oxidative stress.","volume":"9","author":"Hayden","year":"2007","journal-title":"Antiox Redox Signal"},{"key":"2020071612344022900_R18","first-page":"725","article-title":"Ultrastructural islet study of early fibrosis in the Ren 2 rat model of hypertension. Emerging role of the islet pancreatic pericyte-stellate cell.","volume":"8","author":"Hayden","year":"2007","journal-title":"J Pancreas"},{"key":"2020071612344022900_R19","doi-asserted-by":"crossref","first-page":"581","DOI":"10.2337\/diabetes.52.3.581","article-title":"Glucose toxicity in \u03b2-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection.","volume":"52","author":"Robertson","year":"2003","journal-title":"Diabetes"},{"key":"2020071612344022900_R20","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1248\/bpb.24.876","article-title":"Apoptosis and mitochondrial damage in INS-1 cells treated with alloxan.","volume":"24","author":"Sakurai","year":"2001","journal-title":"Biol Pharm Bull"},{"key":"2020071612344022900_R21","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1006\/bbrc.1993.2641","article-title":"Biochemical evidence for nitric oxide formation from streptozotocin in isolated pancreatic islet.","volume":"197","author":"Turk","year":"1993","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071612344022900_R22","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1007\/s00125-005-1761-z","article-title":"Angiotensin II type 1 receptor inhibition markedly improves the blood perfusion, oxygen tension and first phase of glucose-stimulated insulin secretion in revascularised syngeneic mouse islet grafts.","volume":"48","author":"Kampf","year":"2005","journal-title":"Diabetologia"},{"key":"2020071612344022900_R23","doi-asserted-by":"crossref","first-page":"367","DOI":"10.2337\/diabetes.55.02.06.db05-1022","article-title":"Angiotensin II type 1 receptor blockade improves \u03b2-cell function and glucose tolerance in a mouse model of type 2 diabetes.","volume":"55","author":"Chu","year":"2006","journal-title":"Diabetes"},{"key":"2020071612344022900_R24","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/S1074-5521(00)00134-4","article-title":"Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin.","volume":"7","author":"Rahuel","year":"2000","journal-title":"Chem Biol"},{"key":"2020071612344022900_R25","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1097\/00004872-200502000-00025","article-title":"Aliskiren, a novel, orally effective renin inhibitor, lowers blood pressure in marmosets and spontaneously hypertensive rats.","volume":"23","author":"Wood","year":"2005","journal-title":"J Hypertens"},{"key":"2020071612344022900_R26","first-page":"570","article-title":"Differential gene expression of renin and angiotensinogen in the TGR(mREN-2)27 transgenic rat.","author":"Lee","year":"1995"},{"key":"2020071612344022900_R27","doi-asserted-by":"crossref","first-page":"G619","DOI":"10.1152\/ajpgi.00428.2007","article-title":"Daily exercise increases hepatic fatty acid oxidation and prevents steatosis in Otsuka Long-Evans Tokushima Fatty (OLETF) rats","volume":"294","author":"Rector","year":"2008","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"2020071612344022900_R28","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1172\/JCI0214276","article-title":"Pivotal role of the renin\/prorenin receptor in angiotensin II production and cellular responses to renin.","volume":"109","author":"Nguyen","year":"2002","journal-title":"J Clin Invest"},{"key":"2020071612344022900_R29","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1161\/01.HYP.0000215952.91959.4a","article-title":"Prorenin: back into the arena.","volume":"47","author":"Danser","year":"2006","journal-title":"Hypertension"},{"key":"2020071612344022900_R30","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1126\/science.1103160","article-title":"Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes.","volume":"306","author":"Ozcan","year":"2005","journal-title":"Science"},{"key":"2020071612344022900_R31","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/sj.bjp.0702801","article-title":"Pro-oxidant challenge in vivo provokes the onset of NIDDM in the insulin resistant Zucker rat.","volume":"128","author":"Laight","year":"1999","journal-title":"Br Journal Pharmacol"},{"key":"2020071612344022900_R32","doi-asserted-by":"crossref","first-page":"10857","DOI":"10.1073\/pnas.96.19.10857","article-title":"Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants.","volume":"96","author":"Tanaka","year":"1999","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612344022900_R33","doi-asserted-by":"crossref","first-page":"927","DOI":"10.2337\/diabetes.48.4.927","article-title":"Hyperglycemia causes oxidative stress in pancreatic \u03b2-cells of GK rats, a model of type 2 diabetes.","volume":"48","author":"Ihara","year":"1999","journal-title":"Diabetes"},{"key":"2020071612344022900_R34","first-page":"60","article-title":"Sulfonylurea as well as elevated glucose levels stimulate reactive oxygen species production in the pancreatic \u03b2 cell line, MIN6-a role in NADPH oxidase in \u03b2 cells.","volume":"7","author":"Tsubouchi","year":"2005","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071612344022900_R35","first-page":"33","article-title":"The renin-angiotensin system and the exocrine pancreas.","volume":"2","author":"Chappell","year":"2001","journal-title":"J Pancreas"},{"key":"2020071612344022900_R36","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.regpep.2004.02.003","article-title":"The role of pancreatic renin-angiotensin system in acinar digestive enzyme secretion and acute pancreatitis.","volume":"119","author":"Tsang","year":"2004","journal-title":"Regul Pept"},{"key":"2020071612344022900_R37","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0167-0115(02)00226-4","article-title":"Differential effects of saralasin and ramaprilat, the inhibitors of renin-angiotensin system, on cerulean-induced acute pancreatitis.","volume":"111","author":"Tzang","year":"2003","journal-title":"Regul Pept"},{"key":"2020071612344022900_R38","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1053\/gast.2003.50147","article-title":"Angiotensin-converting enzyme inhibitor attenuates pancreatic inflammation and fibrosis in male Wistar Bonn\/Kobori rats.","volume":"124","author":"Kuno","year":"2003","journal-title":"Gastroenterology"},{"key":"2020071612344022900_R39","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1172\/JCI200319774","article-title":"Superoxide-mediated activation of uncoupling protein 2 causes pancreatic \u03b2 cell dysfunction.","volume":"112","author":"Krauss","year":"2003","journal-title":"J Clin Invest"},{"key":"2020071612344022900_R40","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/415096a","article-title":"Superoxide activates mitochondrial uncoupling proteins.","volume":"415","author":"Echtay","year":"2002","journal-title":"Nature"},{"key":"2020071612344022900_R41","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1016\/j.biocel.2005.04.003","article-title":"Role of oxidative stress, endoplasmic reticulum stress, and c-Jun-terminal kinase in pancreatic \u03b2-cell dysfunction and insulin resistance.","volume":"37","author":"Kaneto","year":"2005","journal-title":"Int J Biochem Cell Biol"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/149\/11\/5643\/8997720\/endo5643.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/149\/11\/5643\/8997720\/endo5643.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T20:43:44Z","timestamp":1594932224000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/149\/11\/5643\/2455309"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,7,24]]},"references-count":41,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2008,11,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2008-0070","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,7,24]]}}}