Journal article
Prorenin independently causes hypertension and renal and cardiac fibrosis in cyp1a1-prorenin transgenic rats
Clinical science (1979), Vol.132(12), pp.1345-1363
06/01/2018
DOI: 10.1042/CS20171659
PMCID: PMC6024026
PMID: 29848510
Abstract
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 ± 18 to 138 ± 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 β (TGFβ) 1 (TGFβ1), 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), β-myosin heavy chain (β-MHC), TGFβ1, PAI-1, and collagen in the heart tissue. Furthermore, renal protein levels of p-NF-κB-p65 and monocyte chemoattractant protein-1 (MCP-1), NAPDH oxidases, malondialdehyde (MDA) and 8-isoprostane (8-IP), p-ERK, p-β-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, β-catenin, and Akt-mediated signals.
Details
- Title: Subtitle
- Prorenin independently causes hypertension and renal and cardiac fibrosis in cyp1a1-prorenin transgenic rats
- Creators
- Guangyu Zhou - Division of Nephrology, Department of Internal Medicine, University of Utah Health, Salt Lake City, UT 84112, U.S.AJie Wu - Division of Nephrology, Department of Internal Medicine, University of Utah Health, Salt Lake City, UT 84112, U.S.AChunyan Gu - Division of Nephrology, Department of Internal Medicine, University of Utah Health, Salt Lake City, UT 84112, U.S.ABin Wang - Division of Nephrology, Department of Internal Medicine, University of Utah Health, Salt Lake City, UT 84112, U.S.AE. Dale Abel - Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah Health, Salt Lake City, UT 84112, U.S.AAlfred K Cheung - Division of Nephrology, Department of Internal Medicine, University of Utah Health, Salt Lake City, UT 84112, U.S.AYufeng Huang - Division of Nephrology, Department of Internal Medicine, University of Utah Health, Salt Lake City, UT 84112, U.S.A
- Resource Type
- Journal article
- Publication Details
- Clinical science (1979), Vol.132(12), pp.1345-1363
- Publisher
- Portland Press Ltd
- DOI
- 10.1042/CS20171659
- PMID
- 29848510
- PMCID
- PMC6024026
- ISSN
- 0143-5221
- eISSN
- 1470-8736
- Language
- English
- Date published
- 06/01/2018
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984025268402771
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