Diphenylthiazole-induced changes in renal ultrastructure and enzymology: toxicologic mechanisms in polycystic kidney disease?
The mechanism by which various chemicals induce renal cystic disease is unknown. To examine the early events in cystogenesis the ultrastructure and biochemistry of liver and kidney were analyzed after the administration of a chemical that induces renal cyst formation. Special emphasis was placed on examining potential mechanisms that would account for the observed loss of extracellular proteoglycans. Renal cystic disease was chemically induced in rats by feeding 2-amino-4,5-diphenylthiazole (DPT) for up to 4 weeks. After 4 days of feeding, DPT had induced a 4-fold increase in total urine output relative to diet-restricted control groups. Both groups maintained, but did not gain, weight during the feeding schedule. Cyst formation was localized to the medullary collecting tubules. Relative to diet-restricted controls, rats fed DPT exhibited diminished renal and hepatic catalase activity, but elevated activity for UDP-glucuronosyltransferase. Medulla showed an increase in the specific activities of the enzymes galactosyltransferase and sulfatase B. These enzymological findings correlated with ultrastructural observations of a loss of peroxisomes, proliferation of endoplasmic reticulum and enlargement of the golgi apparatus. Serum and urinary levels of inorganic sulfate were significantly increased in DPT-fed rats relative to controls. Tissue levels of UDP-glucuronic acid and adenosine 3'-phosphate 5'-phosphosulfate were not depressed by DPT feeding. Thus, DPT-induced cyst formation and loss of staining for glycosaminoglycans does not involve gross depletions of UDP-glucuronic acid and adenosine 3'-phosphate 5'-phosphosulfate, mutual cosubstrates for Phase II drug conjugation reactions and glycosaminoglycan synthesis.
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D005966:Glucuronidase / Q000032:analysis; D014453:Glucuronosyltransferase / Q000032:analysis; D006025:Glycosaminoglycans / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D008297:Male; D007690:Polycystic Kidney Diseases / Q000139:chemically induced*; D051381:Rats; D011919:Rats, Inbred Strains; D013431:Sulfates / Q000378:metabolism; D013844:Thiazoles / Q000633:toxicity*; D014535:Uridine Diphosphate Glucuronic Acid / Q000032:analysis
D006025:Glycosaminoglycans; D013431:Sulfates; D013844:Thiazoles; D014535:Uridine Diphosphate Glucuronic Acid; C002886:Bax 439; D006861:Hydrogen Peroxide; D014453:Glucuronosyltransferase; D005966:Glucuronidase