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NDT Advance Access published online on June 2, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp258
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© The Author [2009]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Peroxisome proliferator-activated receptor alpha plays a crucial role in L-carnitine anti-apoptosis effect in renal tubular cells

Hsi-Hsien Chen1,2, Yuh-Mou Sue3, Cheng-Hsien Chen3,4, Yung-Ho Hsu3, Chun-Cheng Hou3, Chung-Yi Cheng3, Shih-Li Lin3, Wei-Lun Tsai3, Tzen-Wen Chen1,2 and Tso-Hsiao Chen3,5

1 Department of Internal Medicine 2 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University 3 Department of Internal Medicine, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan 4 School of Medicine 5 Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan

Correspondence and offprint requests to: Tso-Hsiao Chen; E-mail: hippy{at}tmu.edu.tw



  Abstract

Background. L-carnitine is synthesized mainly in the liver and kidneys from lysine and methionine from dietary sources. Many reports have shown that L-carnitine can protect certain cells against the toxicity of several anticancer and toxic agents, although the detailed mechanism is poorly understood. In this study, we investigated the protective effect of L-carnitine and its molecular mechanism in renal tubular cells undergoing gentamicin-induced apoptosis.

Methods. Rat tubular cell line (NRK-52E) and mice were used as the model system. Gentamicin-induced apoptosis in renal tubular cells was examined using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling. We introduced short interfering RNA transfection and gene-deficient mice to investigate the protective mechanism of L-carnitine.

Results. We found that L-carnitine inhibited gentamicin-induced reactive oxygen species generation and correlative apoptotic pathways, resulting in the protection of NRK-52E cells from gentamicin-induced apoptosis. The treatment of L-carnitine also lessened gentamicin-induced renal tubular cell apoptosis in mice. L-carnitine was found to increase the prostacyclin (PGI2) generation in NRK-52E cells. The siRNA transfection for PGI2 synthase significantly reduced L-carnitine-induced PGI2 and L-carnitine's protective effect. We found that the activity of the potential PGI2 nuclear receptor, peroxisome proliferator-activated receptor alpha (PPAR{alpha}), was elevated by L-carnitine treatment. The siRNA-mediated blockage of PPAR{alpha} considerably reduced the anti-apoptotic effect of L-carnitine. In PPAR{alpha}-deficient mice, L-carnitine treatment also lost the inhibitory effect on gentamicin-induced apoptosis in kidneys.

Conclusions. Based on these findings, we suggest that L-carnitine protects renal tubular cells from gentamicin-induced apoptosis through PGI2-mediated PPAR{alpha} activation.

Keywords: apoptosis; gentamicin; L-carnitine; peroxisome proliferator-activated receptor alpha (PPAR{alpha}); prostacyclin (PGI2)

Received for publication: 20. 8.08
Accepted in revised form: 6. 5.09


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