Renal (pro)renin receptor contributes to development of diabetic kidney disease through transforming growth factor‐β1 – connective tissue growth factor signalling cascade

Abstract

1. Transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) are expressed in renal glomeruli, and contribute to the development of diabetic nephropathy. Recently, we showed that (pro)renin receptor (PRR) is upregulated in the kidneys of the streptozocin (STZ)-induced diabetes rat model. We hypothesized that in the presence of hyperglycaemia, increased renal PRR expression contributes to enhanced TGF-β1-CTGF signalling activity, leading to the development of diabetic kidney disease. 2. In vivo and in vitro studies were carried out in Sprague-Dawley rats and rat mesangial cells (RMC). PRR blockade was achieved in vivo by treating STZ induced diabetes rats with the handle region peptide (HRP) of prorenin and in vitro by HRP or PRR siRNA in RMC. Angiotensin AT1 receptor blockade was achieved by valsartan treatment. 3. Results showed that expression of PRR, TGF-β1 and CTGF were upregulated in diabetic kidneys and RMC exposed to high glucose. Glucose exposure also induced PRR phosphorylation, a process that was inhibited by HRP, valsartan or PRR siRNA. HRP and valsartan significantly attenuated renal TGF-β1 and CTGF expression in diabetic animals and high glucose treated RMC. Similar results were observed in high glucose exposed RMC in response to PRR siRNA. TGF-β receptor blockade decreased CTGF expression in RMC. Combined administration of valsartan and PRR siRNA showed further reduction of TGF-β1 and CTGF expression in RMC. 4. In conclusion, PRR contributes to kidney disease in diabetes through an enhanced TGF-β1-CTGF signalling cascade.