Radical scavenging effect of gliclazide in diabetic rats fed with a high cholesterol diet

Abstract

Background. Gliclazide is a sulphonylurea antidiabetic drug with anti-oxidant effect due to its azabicyclo-octyl ring. We hypothesized that gliclazide may have a beneficial effect on diabetic nephropathy via radical scavenging. Methods. Streptozotocin-induced diabetic rats fed a 4% cholesterol diet [high cholesterol-diabetes mellitus (HC-DM)] (N = 12) were treated with gliclazide (HC-DM + gliclazide) (N = 12) or glibenclamide (HC-DM + glibenclamide) (N = 12) after 2 weeks of the diabetes induction, and normal rat fed with 4% cholesterol served as control [high cholesterol-control (HC-control)] (N = 12). Renal expression of endothelial nitric oxide synthase (eNOS) and intracellular adhesion molecule-1 (ICAM-1), oxidative stress production via nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase and antioxidant enzyme manganese superoxide dismutase (MnSOD) were evaluated at 4 weeks and renal damage was examined at 8 weeks. Results. HC-DM showed significant increase in renal NAD(P)H oxidase and reduction in MnSOD with a significant increase in urinary lipid peroxidation products and H 2O2 excretion compared to HC-control. Gliclazide treatment, but not glibenclamide, significantly reduced the oxidative products and NAD(P)H oxidase. There was no difference in renal eNOS expression between HC-DM and HC-control rats, and only gliclazide treatment enhanced eNOS expression. Renal damage evaluated by increased glomerular macrophage migration via enhanced ICAM-1 expression, mesangial matrix expansion, and albuminuria was significantly increased in HC-DM, and they were ameliorated by gliclazide but not by glibenclamide. Conclusion. Gliclazide reduced oxidative stress in diabetic rats fed a high cholesterol diet with reduction of renal NAD(P)H oxidase expression, enhanced MnSOD and eNOS expression, and had a beneficial effect on glomerular macrophage infiltration and mesangial expansion.