Regulation of TauT by cisplatin in LLC-PK1 renal cells

Abstract

Cisplatin is a commonly used chemotherapeutic agent that has a major limitation because of its nephrotoxicity. Since cisplatin-induced renal injury is mainly confined to the S3 segment of renal proximal tubules-the primary site for renal adaptive regulation of TauT-we hypothesize that TauT functions as an anti-apoptotic gene and plays a role in protecting renal cells from drug-induced nephrotoxicity. In the present study we demonstrated that expression of TauT was significantly reduced by cisplatin (50 muM) in LLC-PK1 cells. Down-regulation of TauT by cisplatin occurs at the transcriptional level in a dose-dependent manner, as demonstrated through a reporter gene driven by the TauT promoter. It appears that cisplatin down-regulates TauT expression, at least in part, through the p53-dependent pathway, since cisplatin induces the p53 expression, which, in turn, represses TauT. Cisplatin induces apoptosis of LLC-PK1 cells in a dose-dependent manner. However, forced over-expression of TauT by stable transfection of a taurine transporter cDNA (pNCT) in LLC-PK1 cells was able to attenuate cisplatin-induced down-regulation of taurine uptake by LLC-PK1 cells and protect renal tubular cells from apoptosis. The mechanism by which TauT serves as an anti-apoptotic gene in cisplatin-induced renal injury remains to be determined, but could relate to taurine-dependent cell volume regulation.