Peroxisomal proliferator-activated receptor-alpha protects renal tubular cells from doxorubicin-induced apoptosis.
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.
Lin
Heng
H
Department of Internal Medicine, Taipei Medical University-Wan Fang Hospital, No 111, Sing-Lung Road, Sec. 3, Wen-Shan District, Taipei City 116, Taiwan.
Hou
Chun-Cheng
CC
Cheng
Ching-Feng
CF
Chiu
Ted-H
TH
Hsu
Yung-Ho
YH
Sue
Yuh-Mou
YM
Chen
Tso-Hsiao
TH
Hou
Hsin-Han
HH
Chao
Ying-Chi
YC
Cheng
Tzu-Hurng
TH
Chen
Cheng-Hsien
CH
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D002460:Cell Line; D051545:Cyclooxygenase 1 / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D019610:Cytoprotection; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species; D014162:Transfection
D000903:Antibiotics, Antineoplastic; D047493:PPAR alpha; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D003577:Cytochrome P-450 Enzyme System; D051545:Cyclooxygenase 1; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase