Alterations in renal cortical phospholipid content induced by gentamicin: time course, specificity, and subcellular...

Increasing evidence suggests that membrane phospholipids are a major site of interaction between gentamicin and renal tubular cells. To help assess the impact of this interaction on renal tubular cell phospholipid metabolism, renal cortical phospholipid levels were assessed serially during treatment with nephrotoxic doses of gentamicin in the rat. Within 15 h of treatment with a single 100 mg/kg dose of gentamicin, significant increases in phosphatidylinositol and phosphatidic acid occurred, and further increases in these acidic phospholipids were seen 24 h after two and four daily doses. No consistent sustained changes were observed in total phospholipid levels or in levels of other phospholipids. None of these gentamicin treatment regimens was associated with wide-spread tubular cell necrosis in the rat at the intervals studied. In contrast, during models of acute renal failure secondary to HgCl2 and glycerol, increases in phosphatidylinositol and phosphatidic acid were found only after the development of wide-spread tubular cell necrosis. Subcellular fractionation studies showed that the increase in phosphatidylinositol produced by gentamicin involved multiple cell membranes, including mitochondria, brush border membranes, endoplasmic reticulum, and lysosomes, suggesting that the effects of gentamicin on renal cortical acidic phospholipid metabolism are not limited to inhibition of intralysosomal degradative processes but, rather, occur in such fashion as to influence the phospholipid composition of multiple subcellular membranes.