Effects of the Combination of an Angiotensin II Antagonist With an HMG-CoA Reductase Inhibitor in Experimental Diabetes

Kidney Int. 2003 Aug;64(2):565-71. doi: 10.1046/j.1523-1755.2003.00127.x.

Abstract

Background: Angiotensin II type 1 (AT1) receptor antagonists and 3-hydroxy-3-methylglutaryl conenzyme A (HMG-CoA) reductase inhibitors have been shown to confer renoprotection. However, the renal effects of the combination of an AT1 receptor antagonist and an HMG-CoA reductase inhibitor in experimental diabetes are unknown.

Methods: Diabetes was induced by injection of streptozotocin in Wistar rats. Diabetic rats were randomly treated with losartan, an AT1 receptor antagonist, or simvastatin, an HMG-CoA reductase inhibitor, as well as the combination of both for eight weeks. Albumin excretion rate (AER) and plasma concentrations of blood urea nitrogen (BUN), creatinine, cholesterol, and triglycerides were measured. Renal injury was evaluated. Immunohistochemical staining of transforming growth factor beta1 (TGF beta 1) and vascular endothelial growth factor (VEGF) were performed.

Results: Increased AER in diabetic rats was attenuated by treatment with either losartan or simvastatin and further reduced by the combination of the two. Elevated plasma concentrations of BUN and creatinine were only reduced by the combination. There was no significant difference in plasma concentrations of cholesterol and triglycerides between control and diabetic rats and neither was influenced by losartan or simvastatin. Kidney pathologic injury was attenuated by losartan, but not simvastatin, compared to diabetic animals. Overexpression of TGF beta 1 and VEGF was observed in the glomeruli of diabetic rats and was attenuated by losartan, simvastatin, or the combination of both to a similar level.

Conclusion: The combination of an angiotensin antagonist with an HMG-CoA reductase inhibitor confers superiority over monotherapies on renal function, as assessed by prevention of albuminuria and rise in plasma BUN and creatinine. However, no advantage of combination therapy was seen with respect to attenuating renal structural injury and renal expression of TGF beta and VEGF in experimental diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / drug therapy
  • Albuminuria / metabolism
  • Angiotensin II Type 1 Receptor Blockers*
  • Animals
  • Antihypertensive Agents / pharmacology*
  • Blood Urea Nitrogen
  • Creatinine / blood
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Nephropathies / drug therapy*
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology
  • Drug Therapy, Combination
  • Female
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Kidney / metabolism
  • Kidney / pathology
  • Losartan / pharmacology*
  • Male
  • Rats
  • Rats, Wistar
  • Simvastatin / pharmacology*
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta1
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Antihypertensive Agents
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Tgfb1 protein, rat
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Vascular Endothelial Growth Factor A
  • Simvastatin
  • Creatinine
  • Losartan