EFFECTS OF CYCLOSPORINE-A ON THE SYNTHESIS, EXCRETION, AND METABOLISMOF ENDOTHELIN IN THE RAT

Increasing evidence suggests that endothelin, a potent vasoconstrictor , is implicated in cyclosporin A (CsA)-induced nephrotoxicity. Increas ed levels of urinary and circulating endothelin have been described in CsA-treated humans and animals. The exact mechanisms by which CsA ind uces these increases are still unknown, and no data indicate whether t hese elevated levels reflect increased synthesis or decreased clearanc e of endothelin. In the present study, we investigated the effects of CsA administration (50 mg/kg per day IP for 6 days) to rats on plasma and urinary levels of endothelin; expression of endothelin-l (ET-1), E T-3, and endothelin-converting enzyme in renal tissue; clearance of in fused I-125-ET-1; and degradation of I-125-ET-1 by recombinant neutral endopeptidase. Rats given CsA for 6 days developed severe renal insuf ficiency, as shown by a 74% decrease in creatinine clearance rate (Ccr ) (P<.006). Ccr was remarkably improved in CsA-treated rats that recei ved bosentan, the combined antagonist of both endothelin A and endothe lin B receptors. Urinary excretion of endothelin increased from an und etectable level to 31.7+/-6.0 pg/24 h (P<.001), and plasma levels of e ndothelin were unchanged (2.8+/-0.2 to 3.1+/-0.2 pg/mL). Reverse trans cription followed by quantitative polymerase chain reaction revealed t hat ET-1 mRNA in the renal medulla increased by 59% (P<.006), whereas the expression of both ET-3 and endothelin-converting enzyme was uncha nged. In other rats, neither acute nor chronic treatment with CsA affe cted either the clearance of I-125-ET-1 from the blood or the renal an d pulmonary uptake of the peptide. Moreover, CsA did not affect the de gradation of I-125-ET-1 by highly purified recombinant neutral endopep tidase, a well-known endothelinase. Taken together, these data suggest that the elevated urinary endothelin levels obtained after CsA treatm ent originate from the kidney and reflect increased renal synthesis of ET-1. Moreover, the production of endothelin appears to be regulated at the mRNA transcription level, and expressions of ET-1 and ET-3 are regulated independently.