Induction of nephrotoxicity by high doses of gentamicin in diabetic rats

Rats with streptozotocin-induced diabetes mellitus (DM) are resistant to aminoglycoside (AG) nephrotoxicity presumably because of defective transport and accumulation of drug by proximal tubular cells. To test this hypothesis we injected DM rats with saline or with gentamicin, 100, 200, and 400 mg/kg per day for 6 days, to determine if the renal cortical concentration of gentamicin could be raised to toxic levels. Nephrotoxicity was assessed by monitoring for evidence of accelerated lipid peroxidation in the renal cortex, for elevation of the serum creatinine concentration, and for evidence of proximal tubular cell injury and necrosis by light and electron microscopy. At 100 mg/kg per day renal cortical gentamicin was 454 +/- 85 micrograms/g. Except for an increase in renal cortical phospholipids these rats manifested no evidence of accelerated lipid peroxidation or elevation of serum creatinine. At 200 mg/kg per day renal cortical gentamicin rose to 636 +/- 20 micrograms/g. These rats manifested mild functional and morphological evidence of toxicity. At 400 mg/kg renal cortical gentamicin rose to 741 +/- 43 micrograms/g. These rats developed severe nephrotoxic injury as manifested by a marked increase of lipid peroxidation evident by an increase of malondialdehyde from a control level of 0.48 +/- 0.02 to 1.72 +/- 0.12 nmole/mg protein, a shift from unsaturated to saturated fatty acids esterified in renal cortical phospholipids, depression of superoxide dismutase and catalase, and a shift from reduced to oxidized glutathione. The serum creatinine rose from a baseline level of 0.24 +/- 0.01 to 0.46 +/- 0.05 mg/dl. Light and electron microscopy revealed enlarged lysosomes distended with typical myeloid bodies and extensive proximal tubular cell necrosis. These observations provide compelling evidence in support of the view that the resistance of DM rats to AG nephrotoxicity is causally linked to the low rate of drug uptake by renal proximal tubular cells. When the renal cortical concentration reaches a critical level, it elicits a pattern of toxic injury indistinguishable from that of nondiabetic rats. Thus, there is nothing inherent to the diabetic state that prevents AGs from causing their usual adverse effects on the metabolism of renal proximal tubular cells once they gain access in sufficient quantity into these cells.