Protective Effect of Angiotensin II Type 1-Receptor-Blocker on Diabetic Nephropathy in Rats: Role of Nephrin

Abstract Background: Angiotensin II-Receptor Blockers (ARBs) has a questionable nephroprotective effect especially in diabetic nephropathy. Nephrin protein molecules exist in the slit diaphragm of the glomerular filtration membrane and control the passage of plasma protein. Aim of Study: To examine the possible role of Nephrin in the pathogenesis of diabetic nephropathy and the protective effect of ATII-RB (candesartan) on diabetic nephropathy. Material and Methods: Thirty-two male rats were used in this experiment. Half of the rats were fed a high-fat diet (HFD) and the other half were fed a standard diet for 4 weeks. A model of diabetic nephropathy (DN) was created by a 35mg/kg intraperitoneal dose of Streptozotocin (STZ) in the HFD-fed rats. Then the rats were divided into four groups (8 rats/group). (1) Normal control (NC) group; (2) Diabetic nephropathy (DN) group; (3) ARB-treated NC group: Normal rats were treated with the ARB (Candesartan Cilexetil), in a dose 0.1mg/kg; (4) ARB-treated DN group: The rats with DN and received the above dose of candesartan for 4 weeks. The urine was collected to measure the urine flow rate, urinary concentrations of Nephrin, creatinine, and protein. Blood samples were used to measure urea, creatinine, glucose, insulin, and the homeostatic model assessment (HOMA-IR). Then renal tissue samples were used to measure Superoxide dismutase (SOD) activity and Malondialdehyde (MDA) in addition to histopathological examination. The mean arterial blood pressure (MABP) was also recorded. Results: Candesartan treatment in the DN group showed significant reductions of glucose, HOMA-IR, amelioration of renal antioxidant system, reductions in creatinine, reduction of proteinuria, reduction of urinary Nephrin, and MABP. Histological improvement was also detected in the form of mild glomerulosclerosis and interstitial fibrosis. The urinary Nephrin was 90 times high in the condition of DN. This huge rise of urinary Nephrin was significantly reduced by Cande-sartan treatment. Moreover, in the DN group the urinary Nephrin level showed a significant correlation with glucose level, serum creatinine, urinary protein-creatinine ratio, and MABP.
Conclusion: ATII-RB could reduce urinary Nephrin ex-cretion and possibly alters its expression through its inhibitory effect on the reactive oxygen species, the Renin-Angiotensin-Aldosterone system and subsequently maintains the normal physiological activity of podocytes in rats with STZ-induced diabetic nephropathy.