Stress-responsive gene TauT and acute kidney injury

Xiaobin Han,Russell W Chesney

doi:10.1186/1423-0127-17-s1-s28

Abstract

BackgroundCisplatin 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).MethodsRegulation of TauT by p53 and c-Jun was determined by reporter gene assay, DNA binding, Western blot analysis, and immunohistochemistry.ResultsTauT 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.ConclusionsOur 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.

Highlights

Cisplatin is a commonly used chemotherapeutic agent that has a major limitation because of its nephrotoxicity
taurine transporter gene (TauT) is directly regulated by c-Jun in renal cells Our studies have shown that TauT is regulated by several transcription factors, including Sp1, WT1, and p53 [14,15,16]
We have found that signals of immunostaining for FasL were higher in cisplatin-treated wt mice, which mainly co-located with p53 and PUMA in the outer stripe of kidney cortex, while FasL was only detected in the kidney medulla of TauT transgenic mice (Figure 4B)

Summary

Introduction

Cisplatin is a commonly used chemotherapeutic agent that has a major limitation because of its nephrotoxicity. We have investigated how TauT is regulated by p53 and c-Jun and its role during acute kidney injury (AKI). Acute kidney injury due to ischemic or toxic renal injury is a common disorder with a mortality of about 50% [1,2]. A vast majority of research in the field has focused on the determination of events and factors that cause renal proximal tubular cell (RPTC) injury and death and lead to the development of AKI. Cisplatin-induced AKI is currently a topic of intense study. As a highly effective chemotherapeutic agent, cisplatin has been used to treat a wide variety of solid tumors [3].

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