Evidence that renal prostaglandin and thromboxane production is stimulated in chronic cyclosporine nephrotoxicity.
Previous reports suggest that cyclosporine (CsA) may have direct effects on arachidonic acid (AA) metabolism in several different tissues. However, the effects of CsA on renal eicosanoid production are unclear. Furthermore, the potential role of changes in renal prostaglandin and thromboxane metabolism in mediating CsA nephrotoxicity is not known. Therefore, in this study, we evaluated the effects of CsA toxicity on the production of AA metabolites by the kidney. In a postischemic, denervated rat model, CsA (50 mg/kg/day) administered for 12-14 days resulted in significant nephrotoxicity with marked decreases in both glomerular filtration rate and renal blood flow. This reduction in renal function was associated with an increase in the renal production of TXB2, PGE2, and 6-PGF1 alpha in vitro. Arachidonic acid significantly stimulated renal eicosanoid production above control values. Increased urinary excretion of TXB2, 2,3-dinorTXB2 (a major TXB2 metabolite), and 6-keto-PGF1 alpha also occurred in rats with CsA nephrotoxicity and reflected the increase in renal production of these eicosanoid products. In contrast, urinary PGE2 excretion was not increased in CsA toxic rats. Thus, CsA nephrotoxicity is associated with specific alterations in renal AA metabolism. Furthermore, alterations in AA metabolism may be important in modulating renal hemodynamics and excretory function in this model. These studies suggest that specific inhibition of vasoconstrictor products of AA metabolism might ameliorate the nephrotoxic effects of CsA.
D000818:Animals; D003524:Cyclosporins / Q000633:toxicity*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007700:Kinetics; D008297:Male; D011453:Prostaglandins / Q000096:biosynthesis* / Q000652:urine; D051381:Rats; D011912:Rats, Inbred ACI; D012039:Regional Blood Flow / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects; D013929:Thromboxane B2 / Q000096:biosynthesis* / Q000652:urine
D003524:Cyclosporins; D011453:Prostaglandins; D013929:Thromboxane B2