[Studies on the mechanisms of renal damages induced by nephrotoxic compounds]

The present study was designed to evaluate the relationship between renal lipid peroxidation and acute renal damage induced by six nephrotoxic compounds: mercuric chloride (MC), glycerol (GL), maleic acid (MA), cephaloridine (CER), gentamicin (GM) and cisplatin (CDDP) in rats. Urine and blood biochemical analyses, determination of renal lipid peroxidation and its scavengers, and histopathological examination were performed in the time or day course after a single dose, or during consecutive administration of these compounds. Moreover, the effects of the antioxidant N,N'-diphenyl-p-phenylene-diamine (DPPD) on the renal damage induced by each compound were studied. 1. MC was administered subcutaneously once at doses of 2 or 4 mg/kg. At a dose of 4 mg/kg, the increase of renal malondialdehyde (MDA) as an index of lipid peroxidation was observed 12 hours after administration. The increase of renal MDA was associated with the development of mild necrosis in proximal straight tubules (PST). Pretreatment of rats with DPPD 600 mg/kg, i.p. ameliorated MC-induced nephrotoxicity. These results indicate that lipid peroxidation plays a significant role in MC-induced renal damage. 2. GL was administered subcutaneously once at doses of 2.5 or 5.0 ml/kg. The increase of MDA was observed on and after 24 hours at a dose of 2.5 ml/kg, 12 hours at a dose of 5.0 ml/kg. These changes were associated with the development of mild necrosis in proximal convoluted tubules (PCT). Pretreatment of rats with DPPD ameliorated GL-induced nephrotoxicity. These results indicate that lipid peroxidation plays a significant role in GL-induced renal damage. 3. MA was administered intraperitoneally once at doses of 100 and 200 mg/kg. Renal MDA did not increase at any observation times. At both doses, vacuole formation, mitochondrial swelling and condensation in PCT were observed 3 hours, and tubular necrosis occurred 3 and 6 hours after administration, which were associated with a decrease of renal glutathione. Pretreatment of rats with DPPD did not ameliorate MA-induced nephrotoxicity. These results suggest that lipid peroxidation does not play a significant role in MA-induced renal damage. 4. CER was administered intravenously once at doses of 500 and 1000 mg/kg. Renal MDA did not increased at any observation times. At both doses, vacuole formation and mitochondrial swelling in PCT were observed 1 hour, and mild necrosis in PCT was induced 6 hours after administration. On the other hand, DPPD ameliorated CER-induced renal histopathological changes. These results indicate that lipid peroxidation play a possible role in CER-induced renal damage. 5. GM was administered subcutaneously on 7 consecutive days at a dose of 40, 80 and 120 mg/kg. Renal MDA increased from first to 7th day at a dose of 120 mg/kg. At all doses, lysosomes which contained many myeloid bodies in PCT were observed 1st day after administration. Daily pretreatment of rats with DPPD 300 mg/kg, i.p. did not affect GM-induced histopathological changes, but ameliorated a part of the urinary biochemical parameters. These results suggest that lipid peroxidation plays a possible role in GM-induced renal damage. 6. CDDP was administered intraperitoneally once at a dose of 4 or 8 mg/kg. Renal MDA increased on 7th day, but at both doses, necrosis in PST had observed 3rd day after administration. Daily pretreatment of rats with DPPD 300 mg/kg, i.p. did not ameliorate CDDP-induced nephrotoxicity. These results suggest that lipid peroxidation does not play a significant role in CDDP-induced renal damage. From these results, lipid peroxidation will be a possible toxicological mechanism of acute renal damage induced by well established nephrotoxic compounds.