Peroxisome Proliferator-Activated Receptor ? Protects Renal Tubular Cells from Gentamicin-Induced Apoptosis via Upregulating Na+/H+ Exchanger NHE1.

ABSTRACT: Peroxisome proliferator-activated receptor (PPAR)-? is a transcription factor that has been reported to inhibit gentamicin-induced apoptosis in renal tubular cells. However, the antiapoptotic mechanism of PPAR? is still unknown. In this study, we found that PPAR? overexpression induced Na+/H+ exchanger-1 (NHE1) expression in the rat renal tubular cells NRK-52E. Beraprost, a PPAR? ligand, also increased NHE1 expression in the renal tubules in normal mice, but not in PPAR? knockout mice. Chromatin immunoprecipitation assays revealed that two PPAR? binding elements were located in the rat NHE1 promoter region. Na+/H+ exchanger activity also increased in the PPAR?-overexpressed cells. Flow cytometry showed that the PPAR?-overexpressed cells were resistant to apoptosis-induced shrinkage. Cariporide, a selective NHE1 inhibitor, inhibited the antiapoptotic effect of PPAR? in the gentamicin-treated cells. The interaction between NHE1 and ezrin/radixin/moesin (ERM) and between ERM and phosphatidylinositol 4,5-bisphosphate in the PPAR?-overexpressed cells was more than in the control cells. ERM short interfering RNA (siRNA) transfection inhibited the PPAR?-induced antiapoptotic effect. PPAR? overexpression also increased the phosphoinositide 3-kinase (PI3K) expression, which is dependent on NHE1 activity. Increased PI3K further increased the phosphorylation of the prosurvival kinase Akt in the PPAR?-overexpressed cells. Wortmannin, a PI3K inhibitor, inhibited PPAR?-induced Akt activity and the antiapoptotic effect. We conclude that PPAR? induces NHE1 expression and then recruits ERM to promote PI3K/Akt-mediated cell survival in renal tubular cells. The application of PPAR? activation reduces the nephrotoxicity of gentamicin and may expand the clinical use of gentamicin.

SUBMITTER: Chen CH 

PROVIDER: S-EPMC4818255 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature