The protective effect of prostacyclin on adriamycin-induced apoptosis in rat renal tubular cells.
Adriamycin-induced nephrosis in rats is a commonly used experimental model for pharmacological studies of human chronic renal diseases. Adriamycin-induced apoptosis of renal tubular cells has been reported in adriamycin-treated rats. In addition, prostacyclin (PGI(2)) is known to have various protective effects on many kinds of cells. To investigate the protective effect of PGI(2) on cells undergoing adriamycin-induced apoptosis, this study selectively augmented PGI(2) production via adenovirus-mediated transfer of genes for cyclooxygenase-1 (COX-1) and prostacyclin synthase (PGIS) (two key enzymes of PGI(2) synthesis) to renal tubular cells. This PGI(2) overexpression protected rat renal tubular cells from adriamycin-induced apoptosis. Ad-COX-1/PGIS transfection was found to reduce the adriamycin-stimulated activities of caspase-3 and caspase-9, inhibit adriamycin-induced release of cytochrome c, elevate the expression of Bcl-x(L), and suppress the activation and translocation of nuclear factor-kappaB (NF-kappaB) in adriamycin-treated renal tubular cells. Our results reveal that selective augmentation of PGI(2) production can protect rat renal tubular cells from adriamycin-induced apoptosis via the NF-kappaB signaling pathway. This implies the therapeutic potential of combined COX-1 and PGIS gene transfer in gene therapy for chronic renal diseases.
Chen
Cheng-Hsien
CH
Department of Internal Medicine, Taipei Medical University, Wan Fang Hospital, Taipei, Taiwan.
Lin
Heng
H
Hsu
Yung-Ho
YH
Sue
Yuh-Mou
YM
Cheng
Tzu-Hurng
TH
Chan
Paul
P
Chen
Tso-Hsiao
TH
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D051545:Cyclooxygenase 1 / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004317:Doxorubicin / Q000009:adverse effects*; D011464:Epoprostenol / Q000096:biosynthesis / Q000502:physiology*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D020287:In Situ Nick-End Labeling; D019746:Intramolecular Oxidoreductases / Q000235:genetics; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D014162:Transfection
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase