Irbesartan (Irb) Treatment Ameliorates Renal Damage in High Protein Fed FHH Rats: Role of L‐Arginine (arg) Pathways

Abstract

The FHH rat is a model of spontaneous glomerulosclerosis, resulting from five renal failure genes (Rf 1‐5), exacerbated by high protein intake. We studied the effects of AT‐1 blockade, via Irb, on arg synthesis and utilization. Arg is synthesized by renal argininosuccinate synthase/lyase (ASS/ASL) and then either consumed within the kidney by arginase II or NOS, or released into the circulation. Arg competes for NOS with ADMA, which is degraded by dimethylarginine dimethylaminohydrolase (DDAH) 1/2. Male FHH rats (6wks old) were put on a 40% casein diet, with (HP+Irb; n=10) or without (HP; n=10) Irb treatment, for 13 wks. Data are summarized in Table (* p<0.05, ** p<0.01, *** p<0.001). HP+Irb rats had reduced proteinuria (UpV mg/24h/100gBW), blood pressure (BP, mmHg), kidney weight (KW, g), glomerulosclerosis index (GSI), and creatinine clearance (CCr, ml/min/100gBW). HP+Irb rats had reduced expression of eNOS (70%) and DDAH2 (65%), higher DDAH1 (120%) and nNOS (>500%) vs. HP. There was no change in the expression of ASS and ASL and Irb reduced arginase II (35%), which allow more arg for NO synthesis. Increased arginase II, and decreased nNOS and DDAH1 expression in HP rats are potential mechanisms for renal injury. These data suggest that Irb may improve renal outcome both by increasing arg supply to the kidney by lowering arginase, and by increasing nNOS expression.