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SELECTIVE ENHANCEMENT OF THROMBOXANE IN MACROPHAGES AND KIDNEYS IN CYCLOSPORINE‐INDUCED NEPHROTOXICITY

Cyclosporine (CsA) associated renal dysfunction is relanted in part to renal vasoconstriction. To identify the role of cyclooxygenase metabolites in the induction of vasoconstriction, we analyzed the effect of CsA on the synthesis of thromboxane (TxA2) prostacyclin (PGI2) and prostaglandin E2 (PGE2) in the kidney and peritoneal macrophages. Groups of rats were pair-fed diets enriched with 20% fish oil (FO) or corn oil (CO) for 4 weeks and then were injected with CsA 12.5 mg/kg/day i.p. for 2 weeks. CsA induced the synthesis of TxA2 and modestly reduced PGE2 and PGI2 in renal cortex and peritoneal macrophages. Feeding rats a diet enriched in FO containing omega-3 fatty acids as compared with CO without these fatty adids suppressed the increase in TxA2 and decreased the vasodilators PGE2 and PGI2 in the kidney and peritoneal macrophages, while modifying the glomerular filtration rate and vacuolization in proximal convoluted tubules characteristic of rodent CsA-associated nephrotoxicity. Thus, CsA-initiated renal vasoconstriction in related to an increase increase in the vasoconstrictive Tx molecule and the reduction in vasodilator metabolites. Intrarenal macrophages represent a likely source of this Tx production. Feeding rats diets containing omega-3 fatty acids, known to be competitive inhibitors of cyclooxygenase metabolites, prevents CsA from selectively increasing TxA2 and preserves renal function.