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  • Title: Peroxisomal proliferator-activated receptor-alpha protects renal tubular cells from doxorubicin-induced apoptosis.
    Author: Lin H, Hou CC, Cheng CF, Chiu TH, Hsu YH, Sue YM, Chen TH, Hou HH, Chao YC, Cheng TH, Chen CH.
    Journal: Mol Pharmacol; 2007 Nov; 72(5):1238-45. PubMed ID: 17671096.
    Abstract:
    Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) 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-alpha on doxorubicin-induced apoptosis and its detailed mechanism in NRK-52E cells and animal models. The mRNA level of PPAR-alpha was found to be reduced by doxorubicin treatment in NRK-52E cells. PPAR-alpha overexpression in NRK-52E cells significantly inhibited doxorubicin-induced apoptosis and the quantity of cleaved caspase-3. Endogenous prostacyclin (PGI(2)) augmentation, which has been reported to protect NRK-52E cells from doxorubicin-induced apoptosis, induced the translocation and activation of PPAR-alpha. The transformation of PPAR-alpha short interfering RNA was applied to silence the PPAR-alpha gene, which abolished the protective effect of PGI(2) augmentation in doxorubicin-treated cells. To confirm the protective role of PPAR-alpha in vivo, PPAR-alpha 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-alpha-deficient mice. In NRK-52E cells, the overexpression of PPAR-alpha elevated the activity of catalase and superoxide dismutase and inhibited doxorubicin-induced reactive oxygen species (ROS). PPAR-alpha overexpression also inhibited the doxorubicin-induced activity of nuclear factor-kappaB (NF-kappaB), which was associated with the interaction between PPAR-alpha and NF-kappaB p65 subunit as revealed in immunoprecipitation assays. Therefore, PPAR-alpha is capable of inhibiting doxorubicin-induced ROS and NF-kappaB activity and protecting NRK-52E cells from doxorubicin-induced apoptosis.
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