PREVENTION OF RENAL FIBROSIS BY SPIRONOLACTONE IN MICE WITH COMPLETE UNILATERAL URETERAL OBSTRUCTION

Abstract

Recent data suggest that aldosterone directly mediates cardiac fibrosis and hypertensive nephrosclerosis. We conducted experiments to determine whether administration of spironolactone, a mineralocorticoid receptor antagonist, reduced renal fibrosis in an experimental model of obstructive uropathy. Complete unilateral ureteral obstruction (UUO) was created surgically in 8 to 10-week-old male C57BL/6 mice by placing sutures around the right ureter. Spironolactone (50 mg/kg/daily) or 1% dimethyl sulfoxide vehicle was administered by subcutaneous injection for 1 to 2 weeks, and renal fibrosis was assessed by measuring trichrome staining and type I collagen deposition in the kidney. UUO lasting 1 week was associated with minimal parenchymal damage and spironolactone had no demonstrable effect. In contrast, administration of the mineralocorticoid antagonist (8 mice) for a 2-week period significantly reduced renal fibrosis in the obstructed kidney, compared to mice given the dimethyl sulfoxide vehicle (9). The beneficial effect of spironolactone treatment was not associated with any changes in serum potassium or aldosterone concentration, or urinary concentrations of sodium or potassium. Administration of spironolactone reduced renal fibrosis in mice with UUO. These findings suggest that clinical trials are warranted to determine the efficacy of aldosterone antagonists in conjunction with angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers as renoprotective agents in patients with obstructive uropathy.