Renal protein degradation: a biochemical target of specific nephrotoxicants.
Protein degradation in the kidney occurs mainly in lysosomes, organelles which may also accumulate nephrotoxic chemicals. The goal of this study was to evaluate the effects of intracellular accumulation of gentamicin, cephaloridine and cisplatin on lysosomal digestion of the protein lysozyme. Gentamicin (15 or 30 mg/kg/day for 3 or 5 days), cisplatin (2.5 or 5 mg/kg) or cephaloridine (500, 1000, 2000 or 2500 mg/kg) was administered ip to male Wistar rats. The main site of the nephrotoxic effects of these compounds was the proximal tubule where these agents differentially affected S1, S2 and/or S3 segments. A 2- and 4-fold increase of the excretion of N-acetyl-beta-D-glucosaminidase (NAG) was observed in the urine from cisplatin- and gentamicin-treated rats, respectively; no change in enzyme excretion occurred after cephaloradine. One hour prior to sacrifice, rat were given 0.3 mg of unlabelled lysozyme in combination with 125I-lysozyme in 0.3 mL saline. Renal cortical slices were prepared and incubated for 15, 30, 60 and 90 min. Release of trichloroacetic acid (TCA) soluble radioactivity into the medium was assumed to quantify lysosomal degradation of lysozyme. Accumulation of p-amino-hippurate (PAH) in renal cortical slices and changes in blood urea nitrogen (BUN) concentration were used as indices of renal damage. TCA-soluble radioactivity increased in the medium from kidney slices from control rats to 50% of the total radioactivity after 90 min incubation. In gentamicin-treated rats, lysozyme degradation was significantly decreased by doses of 15 and 30 mg/kg/day after 3 and 5 days of exposure in the absence of any changes in BUN or PAH accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001806:Blood Urea Nitrogen; D002509:Cephaloridine / Q000633:toxicity; D002945:Cisplatin / Q000633:toxicity; D005839:Gentamicins / Q000633:toxicity; D007457:Iodine Radioisotopes; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D009113:Muramidase / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D010130:p-Aminohippuric Acid / Q000378:metabolism
D005839:Gentamicins; D007457:Iodine Radioisotopes; D011506:Proteins; D009113:Muramidase; D002509:Cephaloridine; D002945:Cisplatin; D010130:p-Aminohippuric Acid