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

Abstract

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 [6]. 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-β,D-glucosamini-dase (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) 30000 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 rules out.