PT  - JOURNAL ARTICLE
AU  - Lin, Heng
AU  - Hou, Chun-Cheng
AU  - Cheng, Ching-Feng
AU  - Chiu, Ted-H.
AU  - Hsu, Yung-Ho
AU  - Sue, Yuh-Mou
AU  - Chen, Tso-Hsiao
AU  - Hou, Hsin-Han
AU  - Chao, Ying-Chi
AU  - Cheng, Tzu-Hurng
AU  - Chen, Cheng-Hsien
TI  - Peroxisomal Proliferator-Activated Receptor-α Protects Renal Tubular Cells from Doxorubicin-Induced Apoptosis
AID  - 10.1124/mol.107.037523
DP  - 2007 Nov 01
TA  - Molecular Pharmacology
PG  - 1238--1245
VI  - 72
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/72/5/1238.short
4100  - http://molpharm.aspetjournals.org/content/72/5/1238.full
SO  - Mol Pharmacol2007 Nov 01; 72
AB  - Peroxisome proliferator-activated receptor-α (PPAR-α) is a transcription factor and has been reported to inhibit cisplatin-mediated proximal tubule cell death. In addition, doxorubicin (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-α on doxorubicin-induced apoptosis and its detailed mechanism in NRK-52E cells and animal models. The mRNA level of PPAR-α was found to be reduced by doxorubicin treatment in NRK-52E cells. PPAR-α overexpression in NRK-52E cells significantly inhibited doxorubicin-induced apoptosis and the quantity of cleaved caspase-3. Endogenous prostacyclin (PGI2) augmentation, which has been reported to protect NRK-52E cells from doxorubicin-induced apoptosis, induced the translocation and activation of PPAR-α. The transformation of PPAR-α short interfering RNA was applied to silence the PPAR-α gene, which abolished the protective effect of PGI2 augmentation in doxorubicin-treated cells. To confirm the protective role of PPAR-α in vivo, PPAR-α activator docosahexaenoic acid (DHA) was administered to doxorubicin-treated mice, and it has been shown to significantly reduce the doxorubicin-induced apoptotic cells in renal cortex. However, this protective effect of DHA did not exist in PPAR-α-deficient mice. In NRK-52E cells, the overexpression of PPAR-α elevated the activity of catalase and superoxide dismutase and inhibited doxorubicin-induced reactive oxygen species (ROS). PPAR-α overexpression also inhibited the doxorubicin-induced activity of nuclear factor-κB (NF-κB), which was associated with the interaction between PPAR-α and NF-κB p65 subunit as revealed in immunoprecipitation assays. Therefore, PPAR-α is capable of inhibiting doxorubicin-induced ROS and NF-κB activity and protecting NRK-52E cells from doxorubicin-induced apoptosis. The American Society for Pharmacology and Experimental Therapeutics