Spironolactone in combination with cilazapril ameliorates proteinuria and renal interstitial fibrosis in rats with anti-thy-1 irreversible nephritis

Blockade of the renin-angiotensin system has been established as a treatment for heart failure with hypertension and left ventricular hypertrophy, and for progressive kidney diseases. The present study was conducted to examine whether spironolactone, a mineralocorticoid receptor antagonist, alone or in combination with cilazapril, an angiotensin converting enzyme (ACE) inhibitor, ameliorates proteinuria and renal lesions in an immune-initiated progressive nephritis model. Wistar rats were uninephrectomized 7 days before injection of anti-Thy-1 monoclonal antibody 1-22-3 to induce progressive glomerulonephritis. The nephritic rats were untreated or treated with spironolactone (400 mg/kg body weight/day), cilazapril (1 mg/kg body weight/day), or both for 10 weeks. Proteinuria was increased in the untreated rats 1 week after nephritis induction and was maintained throughout the experiment. Compared with the untreated animals (212.9 +/- 49.2 mg/day), proteinuria was significantly reduced in the spironolactone-treated group (62.0 +/- 4.0 mg/day, p = 0.0046) and the cilazapril-treated group (71.8 +/- 26.0 mg/day, p = 0.0048) on day 70 after antibody injection. Further reduction of proteinuria (42.4 +/- 4.5 mg/day, p = 0.0019 vs. the untreated group) and less renal cortex interstitial fibrotic change (fibrosis score: 142.0 +/- 18.4 vs. 80.3 +/- 18.5 in the untreated group, p = 0.0123) were detected in the spironolactone plus cilazapril-treated group. Blood pressure did not differ among the three treatment groups. In conclusion, spironolactone ameliorates proteinuria to the same degree as cilazapril, and concomitant use of spironolactone and an ACE inhibitor further suppresses renal disease progression. These data suggest that concomitant treatment with spironolactone and an ACE inhibitor has beneficial effects on immune-initiated progressive kidney disease.