Elevated Prorenin Induces Podocyte Injury and Glomerular Fibrosis in cyp1a1-Prorenin Transgenic Rats

Plasma prorenin is commonly elevated in patients with diabetes and has been associated with the development of albuminuria and progression of diabetic nephropathy. Because albuminuria often reflects podocyte injury, the pathogenic role of prorenin in podocyte dysfunction warrants further investigation. In this study, we examined the association between prorenin and podocyte injury, as well as glomerular fibrosis, using a transgenic rat model in which prorenin is inducibly expressed and secreted from the liver. cyp1a1-prorenin transgenic rats were randomized to receive diets containing increasing concentrations of the gene activator indole-3-carbinol (I3C; 0.05%, 0.15%, or 0.3%) for 4 weeks. Wild-type rats maintained on a normal diet served as controls. I3C administration resulted in a dose-dependent increase in plasma prorenin levels in transgenic rats. Elevated prorenin was associated with increased mean arterial pressure and urinary albumin excretion, accompanied by a dose-dependent reduction in podocyte number and slit diaphragm protein expression, as well as segmental foot process effacement and podocyte hypertrophy. In addition, increased prorenin stimulated renal expression of profibrotic factors and promoted glomerular fibrosis. Treatment with either amlodipine or enalapril for 6 weeks prevented the development of hypertension and partially attenuated podocyte injury, albuminuria, and renal fibrosis, without fully reversing these changes. These protective effects were associated with suppression of NF-κB- and Nox2-mediated inflammatory and oxidative stress pathways. Collectively, these findings demonstrate that prorenin promotes podocyte injury and glomerular fibrosis through mechanisms that are partially dependent on hypertension and angiotensin II but also involve angiotensin II-independent pathways.