{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T05:44:12Z","timestamp":1788587052435,"version":"build-2803163510"},"reference-count":47,"publisher":"Portland Press Ltd.","issue":"12","license":[{"start":{"date-parts":[[2019,7,25]],"date-time":"2019-07-25T00:00:00Z","timestamp":1564012800000},"content-version":"vor","delay-in-days":392,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,6,29]]},"abstract":"<jats:p>Plasma prorenin is commonly elevated in diabetic patients and appears to predict the development of diabetic nephropathy. However, the pathological role of prorenin is unclear. In the present study, a transgenic, inducible, hepatic prorenin-overexpressing rat model was generated and the effect of prorenin in organ injury was examined. Four groups of rats (cyp1a1 prorenin transgenic male and female rats and non-transgenic littermates) were assigned to receive a diet containing 0.3% of the transgene inducer indole-3-carbinol (I3C) for 4 weeks. Plasma prorenin concentration was increased and mean arterial pressure (MAP) increased from 80 \u00b1 18 to 138 \u00b1 17 (mmHg), whereas renal prorenin\/renin protein expression was unchanged, in transgenic rats fed with I3C diet. The intact prorenin, not renin, in plasma and urine samples was further observed by Western blot analysis. Importantly, transgenic rats with high levels of prorenin developed albuminuria, glomerular and tubulointerstitial fibrosis associated with increased expression of transforming growth factor \u03b2 (TGF\u03b2) 1 (TGF\u03b21), plasminogen activator inhibitor-1 (PAI-1), collagen, and fibronectin (FN). These rats also exhibited cardiac hypertrophy determined by echocardiography, with elevated ratio of heart weight to body weight (HW\/BW). Cardiac collagen in interstitial and perivascular regions was prominent, accompanied by the increase in mRNA contents of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), \u03b2-myosin heavy chain (\u03b2-MHC), TGF\u03b21, PAI-1, and collagen in the heart tissue. Furthermore, renal protein levels of p-NF-\u03baB-p65 and monocyte chemoattractant protein-1 (MCP-1), NAPDH oxidases, malondialdehyde (MDA) and 8-isoprostane (8-IP), p-ERK, p-\u03b2-catenin, and p-Akt were dramatically increased in prorenin overexpressing rats. These results indicate that prorenin, without being converted into renin, causes hypertension, renal and cardiac fibrosis via the induction of inflammation, oxidative stress and the ERK, \u03b2-catenin, and Akt-mediated signals.<\/jats:p>","DOI":"10.1042\/cs20171659","type":"journal-article","created":{"date-parts":[[2018,5,30]],"date-time":"2018-05-30T11:05:14Z","timestamp":1527678314000},"page":"1345-1363","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Prorenin independently causes hypertension and renal and cardiac fibrosis in cyp1a1-prorenin transgenic rats"],"prefix":"10.1042","volume":"132","author":[{"given":"Guangyu","family":"Zhou","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Utah Health, Salt Lake City, UT 84112, U.S.A."},{"name":"Division of Nephrology, Department of Internal Medicine, Shengjing Hospital, China Medical University, Shenyang 110004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Utah Health, Salt Lake City, UT 84112, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyan","family":"Gu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Utah Health, Salt Lake City, UT 84112, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Utah Health, Salt Lake City, UT 84112, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.\u00a0Dale","family":"Abel","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah Health, Salt Lake City, UT 84112, U.S.A."},{"name":"Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred\u00a0K.","family":"Cheung","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Utah Health, Salt Lake City, UT 84112, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Utah Health, Salt Lake City, UT 84112, U.S.A."},{"name":"Department of Pathophysiology, University of Nantong College of Medicine, Nantong Shi, Jiangsu 226000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2018,6,28]]},"reference":[{"key":"2021113011034377000_B1","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.1056\/NEJM198505303122202","article-title":"Increased plasma inactive renin in diabetes mellitus. 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