Aim of the study was to evaluate the effect of compound 21 (C21), selective AT2 receptor agonist, in diabetic nephropathy and the potential additive effect of C21, when associated to losartan treatment, on the development of albuminuria and renal fibrosis in Zucker diabetic fatty (ZDF) rats. The experiments lasted 15 weeks (from 5 to 20 weeks of age) and were performed in 40 ZDF rats and 12 control Lean rats. ZDF rats were divided in 4 groups: 1) Nine rats were treated with losartan; 2) Ten rats were treated with C21; 3) Nine rats were treated with losartan plus C21; 4) twelve rats were maintained without any treatment. ZDF rats showed an increase in blood glucose level, albuminuria, renal fibrosis, macrophage infiltration and TNF- expression and a reduction of glomerular nephrin expression compared to control Lean rats. C21 treatment reduced renal glomerular, tubulointerstitial and perivascular fibrosis, and macrophage infiltration and TNF- expression in ZDF rats. C21 treatment caused a decrease in albuminuria in ZDF rats up to 11 weeks of age. Losartan decreased macrophage infiltration, TNF- expression and renal glomerular and perivascular fibrosis, restored glomerular nephrin expression, but did not affect tubulointerstitial fibrosis. Losartan treatment caused a decrease in albuminuria in ZDF rats up to 15 weeks of age. At the end of the protocol, only combination of C21 plus losartan significantly reduced albuminuria in ZDF rats. These data demonstrate that C21 has beneficial effect on diabetic nephropathy, suggesting the combination of C21 and losartan as a novel pharmacological tool to slow the progression of nephropathy in type II diabetes.
American Journal of Physiology: Renal Physiology, 2014, Vol 307, Issue 10