Effect of eplerenone, enalapril and their combination treatment on diabetic nephropathy in type II diabetic rats

Nephrol Dial Transplant. 2009 Jan;24(1):73-84. doi: 10.1093/ndt/gfn448. Epub 2008 Aug 5.


Background: Recent data suggest that aldosterone antagonists have beneficial effects on diabetic nephropathy. In this study, we investigated the dose-dependent effect of eplerenone and a combined treatment with eplerenone and enalapril compared with each drug alone on renal function in type II diabetic rats. To further explore the molecular mechanism of action of combination therapy, we also performed in vitro study.

Methods: The animals were divided into six groups as follows: normal control Long-Evans Tokushima Otsuka (LETO) rats, Otsuka Long-Evans Tokushima Fatty (OLETF) rats, OLETF rats treated with low dose of eplerenone (50 mg/kg/day), OLETF rats treated with high dose of eplerenone (200 mg/kg/day), OLETF rats treated with enalapril (10 mg/kg/day) and OLETF rats treated with a combination of both drugs (eplerenone 200 mg/kg/day and enalapril 10 mg/kg/day) for 6 months.

Results: Treatment of OLETF rats had no significant effect on body weight, kidney weight and blood glucose levels. However, urinary albumin excretion, glomerular filtration rate and glomerulosclerosis were significantly improved in the enalapril group and improvement was observed in a dose-dependent manner in the eplerenone groups; the most dramatic decreases were observed in the combination group. In accordance with these findings, renal expressions of TGF-beta1, type IV collagen and PAI-1 were also markedly decreased in the treatment groups, with the combined treatment providing the most significant level of improvement. In cultured mesangial cells, combined treatment resulted in an additive decrease in TGF-beta1, PAI-1 and collagen gene expressions and protein production induced by high glucose and aldosterone stimulation.

Conclusions: Aldosterone receptor antagonism provided additional benefits beyond blockade of the renin-angiotensin system in type II diabetic nephropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / drug therapy
  • Angiotensin-Converting Enzyme Inhibitors / administration & dosage
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Animals
  • Base Sequence
  • Collagen Type IV / genetics
  • Collagen Type IV / metabolism
  • DNA Primers / genetics
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetes Mellitus, Type 2 / physiopathology
  • Diabetic Nephropathies / drug therapy*
  • Diabetic Nephropathies / pathology
  • Diabetic Nephropathies / physiopathology
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • Enalapril / administration & dosage
  • Enalapril / therapeutic use*
  • Eplerenone
  • Extracellular Matrix Proteins / blood
  • Extracellular Matrix Proteins / urine
  • Gene Expression / drug effects
  • Glomerular Filtration Rate / drug effects
  • In Vitro Techniques
  • Male
  • Mesangial Cells / drug effects
  • Mesangial Cells / metabolism
  • Mineralocorticoid Receptor Antagonists / administration & dosage
  • Mineralocorticoid Receptor Antagonists / therapeutic use
  • Plasminogen Activator Inhibitor 1 / genetics
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Rats
  • Rats, Inbred OLETF
  • Renin-Angiotensin System / drug effects
  • Spironolactone / administration & dosage
  • Spironolactone / analogs & derivatives*
  • Spironolactone / therapeutic use
  • Transforming Growth Factor beta / blood
  • Transforming Growth Factor beta / urine
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism


  • Angiotensin-Converting Enzyme Inhibitors
  • Collagen Type IV
  • DNA Primers
  • Extracellular Matrix Proteins
  • Mineralocorticoid Receptor Antagonists
  • Plasminogen Activator Inhibitor 1
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • betaIG-H3 protein
  • Spironolactone
  • Eplerenone
  • Enalapril