Prorenin independently causes hypertension and renal and cardiac fibrosis in cyp1a1-prorenin transgenic rats

In this 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 nontransgenic 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 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 TGFß1, PAI-1, collagen and fibronectin. These rats also exhibited cardiac hypertrophy determined by echocardiography, with elevated ratio of heart weightto body weight. Cardiac collagen in interstitial and perivascular regions was prominent, accompanied by the increases in mRNA contents of ANP, BNP, ß-MHC, TGFß1, PAI-1 and collagen in the heart tissue. Furthermore, renal protein levels of phospho-NF-B-p65 and MCP-1, NAPDH oxidases, MDA and 8-isoprostane, phospho-ERK, phospho-ß-catenin and phospho-Akt were dramatically increased in prorenin overexpressing rats. These results indicate that prorenin, without being converted to reni...
Source: Clinical Science - Category: Biomedical Science Authors: Tags: PublishAheadOfPrint Source Type: research