Angiotensin receptor blockade and glucagon like peptide‐1 receptor activation ameliorates NADPH oxidase 4‐associated oxidative injury in insulin‐resistant rats

Abstract

Diabetic nephropathy is associated with oxidative stress and increased renal NADPH oxidase 4 protein expression. Glucagon‐like peptide‐1 receptor (GLP‐1r) activation decreases glomerular NOX 4 expression and albumin excretion in streptozotocin‐induced diabetic rats. Angiotensin receptor type 1 (AT1) blockade improves renal oxidative injury via downregulation of NOX 4 and reducing urinary albumin excretion. To test the hypothesis that the combination of GLP‐1r activation and AT1 blockade decreases oxidative stress and subsequent kidney damage, we measured renal NOX 4 protein expression and albumin excretion in five rat groups: 1) untreated, lean LETO (n=7), 2) untreated, obese OLETF (n=9), 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan /kg/d; n=9), 4) OLETF + GLP‐1 mimetic (Exe; 10 ug exenatide/kg/d; n=7), and 5) OLETF + ARB + exenatide (combo; n=6). Albumin excretion increased in OLETF compared to LETO; whereas, ARB and Exe decreased it, and combo treatment decreased it further. Renal NOX 4 protein expression increased 23% in OLETF compared to LETO. Exe and ARB decreased NOX 4 protein expression in OLETF rats by 18% and 14% respectively, while the combo treatment decreased it further by 24%. These data suggest that AT1 blockade and GLP‐1r activation ameliorate oxidative renal injury, highlighting the impact of the activation of these receptors in the pathogenesis of diabetes‐associated renal impairments.