Abstract: TH-PO678

Elevated Prorenin Accelerates the Development of Diabetic Nephropathy in STZ-Induced Cyp1a1-Prorenin Transgenic Rats

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Gu, Chunyan, University of Utah, Salt Lake City, Utah, United States
  • Cheung, Alfred K., University of Utah, Salt Lake City, Utah, United States
  • Huang, Yufeng, University of Utah, Salt Lake City, Utah, United States
Background

Elevated plasma prorenin levels are commonly found in diabetic patients and appear to predict the development of diabetic nephropathy (DN). However, the potential pathological role of prorenin in diabetes is unclear. In this study, a transgenic, inducible, hepatic prorenin-overexpressing rat model (cyp1a1-prorenin transgenic rat, TG) was generated and then a model of STZ-induced diabetic cyp1a1-prorenin transgenic rat was established to mimic diabetic patients with elevated plasma prorenin.

Methods

Four transgenic groups (5 rats per group): TG controls, STZ-induced diabetic TG rats, and STZ-induced diabetic TG rats treated with either amlodipine (AM, 10mg/kg/d by daily gavage) or enalapril (Ena, 200mg/L in drinking water), were assigned to receive a diet containing 0.15% of the gene activator indole-3-carbinonl (I3C) started at 2wks after diabetes was confirmed (BG>250 mg/dl). Four corresponding groups of 5 wild-type (WT) rats receiving same treatments served as WT controls. Treatments were given at the same as I3C was given for 6 wks. Animals in all groups were sacrificed at 8 wks after induction of diabetes.

Results

Diabetic WT rats had normal blood pressure but developed microalbuminuria and had kidney hypertrophy and mildly increased glomerular ECM accumulation. Diabetic TG rats with elevated plasma prorenin levels showed hypertension and much worsen features of DN when compared with the diabetic WT animals or non-diabetic transgenic rats, including worsen albuminuria, kidney hypertrophy, enhanced podocyte foot effacement and glomerulosclerosis. Furthermore, increased prorenin in diabetes further stimulated renal cellular signals of Nox2, p47phox and NF-kB-p65, which have been shown to contribute to the development of DN. Treatment with either amlodipine or enalapril had no effect on blood glucose levels, but prevented the development of hypertension and ameliorated, but did not prevented, the development of renal fibrosis, related pro-fibrotic signals and podocyte injury.

Conclusion

These results indicate that prorenin accelerates the development of DN, which is only partially dependent on prorenin-induced hypertension and angiotensin II’s action. These results may suggest the involvement of additional angiotensin II-independent effects of prorenin in DN.

Funding

  • Other NIH Support