Eplerenone potentiates the antiproteinuric effects of enalapril in experimental nephrotic syndrome

Am J Physiol Renal Physiol. 2008 Mar;294(3):F628-37. doi: 10.1152/ajprenal.00524.2007. Epub 2007 Dec 19.

Abstract

Nephrotic syndrome (NS) is a clinical state characterized by massive proteinuria and edema. It is believed that nephrin and podocin are involved in the development of proteinuria. The proteinuria and effects of eplerenone alone or combined with enalapril on nephrin/podocin abundance in rats with NS have not yet been studied. Therefore, the present study was designed to examine the early (beginning 2 days before NS induction) and late (beginning 2 wk after NS induction) effects of eplerenone and enalapril, alone or combined, on proteinuria and nephrin/podocin abundance in rats with adriamycin-induced NS. Adriamycin caused a significant increase in daily protein excretion (U(pr)V; from 26.96 +/- 3.43 to 958.57 +/- 56.7 mg/day, P < 0.001) and cumulative proteinuria [from 900.33 +/- 135.5 to 22,490.62 +/- 931.26 mg (P < 0.001)] during 6 wk. Early treatment with enalapril significantly decreased U(pr)V from 958.6 +/- 56.7 to 600.31 +/- 65.13 mg/day (P < 0.001) and cumulative proteinuria to 12,842.37 +/- 1,798.17 mg/6 wk (P < 0.001). Similarly, early treatment with eplerenone produced a profound antiproteinuric effect: U(pr)V decreased from 958.57 +/- 56.7 to 593.38 +/- 21.83 mg/day, P < 0.001, and cumulative proteinuria to 16,601.84 +/- 1,334.31 mg/6 wk; P < 0.001. An additive effect was obtained when enalapril and eplerenone were combined: U(pr)V decreased from 958.57 +/- 56.69 to 424.17 +/- 38.54 mg/day, P < 0.001, and cumulative protein excretion declined to 10,252.88 +/- 1,011.3 mg/6 wk, P < 0.001. These antiproteinuric effects were associated with substantial preservation of glomerular nephrin and podocin. In contrast, late treatment with either enalapril or eplerenone alone or combined mildly decreased U(pr)V and cumulative proteinuria. Thus pretreatment with eplerenone or enalapril is effective in reducing daily and cumulative protein excretion and preservation of nephrin/podocin. More profound antiproteinuric effects were obtained when enalapril and eplerenone were combined.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / drug therapy
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
  • Animals
  • Blood Pressure / drug effects
  • Blood Urea Nitrogen
  • Drug Synergism
  • Electrolytes / blood
  • Enalapril / pharmacology
  • Enalapril / therapeutic use*
  • Eplerenone
  • Immunohistochemistry
  • Lipids / blood
  • Male
  • Mineralocorticoid Receptor Antagonists / pharmacology
  • Mineralocorticoid Receptor Antagonists / therapeutic use*
  • Nephrotic Syndrome / drug therapy*
  • Proteinuria / drug therapy*
  • Rats
  • Rats, Sprague-Dawley
  • Spironolactone / analogs & derivatives*
  • Spironolactone / pharmacology
  • Spironolactone / therapeutic use

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Electrolytes
  • Lipids
  • Mineralocorticoid Receptor Antagonists
  • Spironolactone
  • Eplerenone
  • Enalapril