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Peroxisomal Proliferator-Activated Receptor- Protects Renal Tubular Cells from Doxorubicin-Induced Apoptosis

Department of Internal Medicine, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan (C.-C.H., Y.-H.H., Y.-M.S., T.-H.C., T.-H.C., C.-H.C.); Graduate Institute of Pharmacology & Toxicology and Department of Medicine, Tzu Chi University, Hualien, Taiwan (H.L., C.-F.C., T.-H.Chiu); Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (H.L., C.-F.C., H.-H.H., Y.-C.C.); and Department of Pediatrics, Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan (C.-F.C.)

Peroxisome proliferator-activated receptor- (PPAR-) 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- on doxorubicin-induced apoptosis and its detailed mechanism in NRK-52E cells and animal models. The mRNA level of PPAR- was found to be reduced by doxorubicin treatment in NRK-52E cells. PPAR- 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-. The transformation of PPAR- short interfering RNA was applied to silence the PPAR- gene, which abolished the protective effect of PGI₂ augmentation in doxorubicin-treated cells. To confirm the protective role of PPAR- in vivo, PPAR- 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--deficient mice. In NRK-52E cells, the overexpression of PPAR- elevated the activity of catalase and superoxide dismutase and inhibited doxorubicin-induced reactive oxygen species (ROS). PPAR- overexpression also inhibited the doxorubicin-induced activity of nuclear factor-B (NF-B), which was associated with the interaction between PPAR- and NF-B p65 subunit as revealed in immunoprecipitation assays. Therefore, PPAR- is capable of inhibiting doxorubicin-induced ROS and NF-B activity and protecting NRK-52E cells from doxorubicin-induced apoptosis.

Address correspondence to: Dr. Cheng-Hsien Chen, Nephrology Division, Department of Internal Medicine, Taipei Medical University-Wan Fang Hospital, No 111, Sing-Lung Road, Sec. 3, Wen-Shan District, Taipei City 116, Taiwan. E-mail: hippy{at}tmu.edu.tw