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.