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First published on August 1, 2007; DOI: 10.1124/mol.107.037523

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Received for publication April 30, 2007.
Revised August 1, 2007.
Accepted for publication August 1, 2007.

Peroxisomal proliferator-activated receptor-alpha (PPAR-{alpha}) protects renal tubular cells from adriamycin-induced apoptosis

Heng Lin 1, Chun-Cheng Hou 2, Ching-Feng Cheng 3, Ted-H Chiu 1, Yung-Ho Hsu 2, Yuh-Mou Sue 2, Tso-Hsiao Chen 2, Hsin-Han Hou 4, Ying-Chi Chao 4, Tzu-Hurng Cheng 2, Cheng-Hsien Chen 2*

1 Graduate Institute of Pharmacology & Toxicology and Department of Medicine, Tzu Chi University 2 Department of Internal Medicine, Taipei Medical University-Wan Fang Hospital 3 Department of Pediatrics, Tzu Chi General Hospital, Taipei Branch 4 Institute of Biomedical Sciences, Academia Sinica

* Address correspondence to: E-mail: hippy{at}tmu.edu.tw

Abstract

Peroxisome proliferator-activated receptor-alpha (PPAR-{alpha}) is a transcription factor and has been reported to inhibit cisplatin-mediated proximal tubule cell death. Additionally, Adriamycin-induced nephrosis in rats is a commonly used experimental model for pharmacological studies of human chronic renal diseases. In this study, we investigated the protective effect of PPAR-{alpha} on adriamycin-induced apoptosis and its detailed mechanism in NRK-52E cells and animal models. The transcriptional level of PPAR-{alpha} was found to be reduced by adriamycin treatment in NRK-52E cells. PPAR-{alpha} overexpression in NRK-52E cells significantly inhibited adriamycin-induced apoptosis and the quantity of cleaved caspase-3. Endogenous prostacyclin (PGI2) augmentation, which has been reported to protect NRK-52E cells from adriamycin-induced apoptosis, induced the translocation and activation of PPAR-{alpha}. The transformation of PPAR-{alpha} siRNA was applied to silence PPAR-{alpha} gene, which abolished the protective effect of PGI2 augmentation in adriamycin-treated cells. To confirm the protective role of PPAR-{alpha} in vivo, PPAR-{alpha} activator docosahexaenoic acid (DHA) was administered to adriamicin-treated mice, and it has been shown to significantly reduce the adriamycin-induced apoptotic cells in renal cortex. However, this protective effect of DHA didn't exist in PPAR-{alpha}-deficient mice. In NRK-52E cells, the overexpression of PPAR-{alpha} elevated the activity of catalase and superoxide dismutase, and inhibited adriamycin-induced ROS. PPAR-{alpha} overexpression also inhibited the adriamycin-induced activity of NF-{kappa}B, which was associated with the interaction between PPAR-{alpha} and NF-{kappa}B p65 subunit as revealed in immunoprecipitation assays. Therefore, PPAR-{alpha} is capable of inhibiting adriamycin-induced ROS and NF-{kappa}B activity, and protecting NRK-52E cells from adriamycin-induced apoptosis.


Key words: PPARs, NFkappaB, Apoptosis, Oxidative stress




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