Mechanisms for protective effects of free radical scavengers on gentamicin-mediated nephropathy in rats.

Studies were performed to examine the mechanisms for the protective effects of free radical scavengers on gentamicin (GM)-mediated nephropathy. Administration of GM at 40 mg/kg sc for 13 days to rats induced a significant reduction in renal blood flow (RBF) and inulin clearance (CIn) as well as marked tubular damage. A significant reduction in urinary guanosine 3',5'-cyclic monophosphate (cGMP) excretion and a significant increase in renal cortical renin and endothelin-1 contents were also observed in GM-mediated nephropathy. Superoxide dismutase (SOD) or dimethylthiourea (DMTU) significantly lessened the GM-induced decrement in CIn. The SOD-induced increase in glomerular filtration rate was associated with a marked improvement in RBF, an increase in urinary cGMP excretion, and a decrease in renal renin and endothelin-1 content. SOD did not attenuate the tubular damage. In contrast, DMTU significantly reduced the tubular damage and lipid peroxidation, but it did not affect renal hemodynamics and vasoactive substances. Neither SOD nor DMTU affected the renal cortical GM content in GM-treated rats. These results suggest that 1) both SOD and DMTU have protective effects on GM-mediated nephropathy, 2) the mechanisms for the protective effects differ for SOD and DMTU, and 3) superoxide anions play a critical role in GM-induced renal vasoconstriction.