Stress-responsive gene TauT and acute kidney injury.
BACKGROUND
Cisplatin is a commonly used chemotherapeutic agent that has a major limitation because of its nephrotoxicity. We have demonstrated that cisplatin down-regulates the expression of the taurine transporter gene (TauT) in renal cells and that forced overexpression of TauT protects against cisplatin-induced apoptosis in renal cells in vitro and in vivo. In the present study, we have investigated how TauT is regulated by p53 and c-Jun and its role during acute kidney injury (AKI).


METHODS
Regulation of TauT by p53 and c-Jun was determined by reporter gene assay, DNA binding, Western blot analysis, and immunohistochemistry.


RESULTS
TauT was down-regulated by p53 and up-regulated by c-Jun. Two potential binding sites for c-Jun were identified in the promoter region of TauT. Inhibition of c-Jun N-terminal kinase (JNK) enhanced TauT promoter activity. Overexpression of TauT protects against cisplatin-induced kidney injury in a TauT transgenic mouse model.


CONCLUSIONS
Our findings suggest that TauT plays a critical role in renal function. Expression of TauT is negatively regulated by p53 and positively regulated by c-Jun, which is mediated by the JNK signaling pathway. The outcome level of TauT may determine the fate of renal cells during stress-induced AKI.
Han
Xiaobin
X
Department of Pediatrics, University of Tennessee Health Science Center, and the Children's Foundation Research Center at Le Bonheur Children's Medical Center, Memphis, Tennessee, USA. xhan@uthsc.edu
Chesney
Russell W
RW
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D016158:Genes, p53; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000502:physiology; D013654:Taurine / Q000378:metabolism; D000099247:Taurine Transporters
D000970:Antineoplastic Agents; D002945:Cisplatin; D048031:JNK Mitogen-Activated Protein Kinases; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D013654:Taurine; D000099247:Taurine Transporters
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