Nitric oxide-induced regulation of renal organic cation transport after renal ischemia-reperfusion injury

Abstract

Renal organic cation transporters are downregulated by nitric oxide (NO) in rat endotoxemia. NO generated by inducible NO synthase (iNOS) is substantially increased in the renal cortex after renal ischemia-reperfusion (I/R) injury. Therefore, we investigated the effects of iNOS-specific NO inhibition on the expression of the organic cation transporters rOct1 and rOct2 (Slc22a1 and Slc22a2, respectively) after I/R injury both in vivo and in vitro. In vivo, N6-(1-iminoethyl)-l-lysine (l-NIL) completely inhibited NO generation after I/R injury. Moreover, l-NIL abolished the ischemia-induced downregulation of rOct1 and rOct2 as determined by qPCR and Western blotting. Functional evidence was obtained by measuring the fractional excretion (FE) of the endogenous organic cation serotonin. Concordant with the expression of the rate-limiting organic cation transporter, the FE of serotonin decreased after I/R injury and was totally abolished by l-NIL. In vitro, ischemia downregulated both rOct1 and rOct2, which were also abolished by l-NIL; the same was true for the uptake of the organic cation MPP. We showed that renal I/R injury downregulates rOct1 and rOct2, which is most probably mediated via NO. In principle, this may be an autocrine effect of proximal tubular epithelial cells. We conclude that rOct1, or rOct1 and rOct2 limit the rate of the renal excretion of serotonin.