Involvement of vascular endothelial nitric oxide synthase in development of experimental diabetic nephropathy in rats

Mol Cell Biochem. 2011 Aug;354(1-2):57-66. doi: 10.1007/s11010-011-0805-6. Epub 2011 Apr 6.

Abstract

Endothelial nitric-oxide synthase (eNOS) acts as a common pathogenic pathway in diabetic nephropathy (DN). However, its functional consequences are still not fully understood. Caveolin, a membrane protein, inhibits the eNOS by making caveolin-eNOS complex, and its expression is upregulated during diabetes mellitus (DM). This study was designed to determine the role of caveolin in eNOS-mediated NO synthesis and release in DN. DM in rat was induced by feeding of high-fat diet (HFD) for 2 weeks, followed by single dose of streptozotocin (STZ) (35 mg/kg, ip) further followed by HFD for further 8 weeks. Serum nitrite/nitrate ratio was measured to determine the plasma level of NO. Diabetic rat, after 6 weeks of STZ, developed elevated level of BUN, protein in urine, urinary output, serum creatinine, serum cholesterol, kidney weight, kidney weight/body weight, and renal cortical collagen content, while serum nitrite/nitrate concentration was significantly decreased as compared to normal control group. Treatment with sodium nitrite (NO donor), L: -arginine (NO precursor), daidzein (caveolin inhibitor), and combination of L: -arginine and daidzein for 2 weeks markedly attenuated these changes and increased serum nitrite/nitrate ratio. However, treatment with L-NAME, a eNOS inhibitor, significantly attenuated the L: -arginine-, daidzein-, or combination of L: -arginine and daidzein-induced ameliorative effects in DN. The finding of this study suggests that caveolin plays a vital role in the eNOS-mediated decrease in renal level of NO, which may be responsible for the development of DN in rats.

MeSH terms

  • Animals
  • Arginine / pharmacology
  • Blood Glucose / drug effects
  • Blood Urea Nitrogen
  • Body Weight
  • Caveolin 1 / antagonists & inhibitors
  • Cholesterol / blood
  • Collagen / metabolism
  • Creatinine / blood
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / physiopathology*
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / physiopathology*
  • Dietary Fats
  • Endothelium, Vascular / metabolism*
  • Isoflavones / pharmacology
  • Kidney / metabolism
  • Kidney / pathology
  • Male
  • Nitric Oxide Synthase Type III / metabolism*
  • Nitrites / blood
  • Organ Size
  • Proteinuria
  • Rats
  • Rats, Wistar
  • Sodium Nitrite / pharmacology
  • Urine

Substances

  • Blood Glucose
  • Cav1 protein, rat
  • Caveolin 1
  • Dietary Fats
  • Isoflavones
  • Nitrites
  • daidzein
  • Collagen
  • Arginine
  • Cholesterol
  • Creatinine
  • Nitric Oxide Synthase Type III
  • Sodium Nitrite