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

Kidney Int. 2004 Mar;65(3):951-60. doi: 10.1111/j.1523-1755.2004.00470.x.

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 H2O2 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure
  • Cholesterol, Dietary / pharmacology*
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetic Nephropathies / drug therapy*
  • Diabetic Nephropathies / metabolism
  • Free Radical Scavengers / pharmacology*
  • Gliclazide / pharmacology*
  • Glyburide / pharmacology
  • Glycated Hemoglobin A / metabolism
  • Hypoglycemic Agents / pharmacology*
  • Intercellular Adhesion Molecule-1 / metabolism
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Macrophages / pathology
  • Male
  • NADPH Oxidases / metabolism
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type III
  • Nitrites / metabolism
  • Oxidative Stress / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Superoxide Dismutase / metabolism

Substances

  • Cholesterol, Dietary
  • Free Radical Scavengers
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Nitrites
  • Intercellular Adhesion Molecule-1
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • Superoxide Dismutase
  • NADPH Oxidases
  • Gliclazide
  • Glyburide