New morphological changes induced by FK506 in a short period in the rat kidney and the effect of superoxide dismutase and OKY-046 on THEM: the relationship of FK506 nephrotoxicity to lipid peroxidation and change in production of thromboxane A2 in the kidney.
Juxtaglomerular (JG) hyperplasia and tubular damage along with a decrease in the urine creatinine level induced by FK506 in rat kidney have already been reported in previous paper by us. In this paper, we document the relationship of FK506 nephrotoxicity to the change in the production of thromboxane (Tx) A2 and the lipid peroxidation of the cellular membrane in the rat kidney in order to clarify its morphogenesis. The urinary excretion of TxB2 increased with FK506 administration even on day 1 (P < 0.02). Histologically, OKY-046 (thromboxane synthetase inhibitor) decreased tubular damage, although JG hyperplasia was not eradicated, while biochemically the excretion of TxB2 decreased significantly (P < 0.02), and both the decrease in the urine creatinine level and the increase in the N-acetyl-beta,D-glucosaminidase (NAG) index were relatively smaller. Although the FK506-induced morphological and biochemical changes could not be prevented by the continuous administration of superoxide dismutase (SOD) 30,000 U/kg daily, the malondialdehyde content in renal tissue removed 1 h after FK506 administration had increased. These data suggest that FK506 nephrotoxicity is related to the change in the production of TxA2 and lipid peroxidation of the cellular membrane. However, other mechanisms such as the involvement of sympathomimetic effects of FK506 and other vasoconstrictive factors cannot be ruled out.
Yamada
K
K
Department of Pathology, Nippon Medical School, Tokyo, Japan.
Sugisaki
Y
Y
Suzuki
S
S
Akimoto
M
M
Amemiya
H
H
Yamanaka
N
N
D000118:Acetylglucosaminidase / Q000378:metabolism; D000818:Animals; D003404:Creatinine / Q000652:urine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006965:Hyperplasia; D007668:Kidney / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology; D008689:Methacrylates / Q000494:pharmacology*; D051381:Rats; D013482:Superoxide Dismutase / Q000494:pharmacology*; D016559:Tacrolimus / Q000633:toxicity*; D013929:Thromboxane B2 / Q000652:urine*
D004791:Enzyme Inhibitors; D008689:Methacrylates; D013929:Thromboxane B2; D003404:Creatinine; D013482:Superoxide Dismutase; D000118:Acetylglucosaminidase; C034364:ozagrel; D016559:Tacrolimus