Studies were performed to examine the effect of desoxycorticosterone acetate (DOCA) treatment plus isotonic saline drinking on gentamicin (GM)-mediated nephropathy in rats. GM, 40 mg/kg/day, was subcutaneously injected for 13 days following a 5-week treatment with water drinking or DOCA (10 mg/kg/week) plus saline drinking. Twenty-four hours after the last injection of GM, renal blood flow (RBF) and Cin decreased to approximately 69% and 52% of the control values in water-drinking GM-treated rats, respectively, but was well maintained in DOCA plus saline-drinking GM-treated animals. There was no significant difference in morphologic tubular injury or the renal cortical GM content between GM-treated groups. Saline drinking alone (1% saline, 5 weeks) lessened neither GM-induced reduction in GFR nor tubular damage. Body weight loss occurred following GM injection in the water-drinking group but not in the DOCA plus saline-drinking and saline-drinking-alone groups. DOCA plus saline drinking significantly suppressed the plasma renin activity (PRA) but saline drinking alone did not. A significant inverse correlation was found between PRA and Cin in water-drinking GM-treated and untreated rats. The data suggest that the beneficial effect of DOCA plus saline drinking is associated with renin-angiotensin suppression rather than with the renal GM content or well-maintained hydration.