Suppression of Apoptosis by All-trans-Retinoic Acid

Abstract

Retinoic acid induces apoptosis of various cells, whereas little is known about its anti-apoptotic poten-tial. In this report, we describe an anti-apoptotic prop-erty of all-trans-retinoic acid (t-RA) in mammalian cells. Mesangial cells exposed to hydrogen peroxide (H 2 O 2) exhibited shrinkage of the cytoplasm, membrane bleb-bing, condensation of nuclei, and DNA fragmentation. Pretreatment with t-RA attenuated the morphologic and biochemical hallmarks of apoptosis. t-RA also inhib-ited apoptosis of mesangial cells triggered by pyrroli-dine dithiocarbamate, whereas it did not prevent tumor necrosis factor-␣-induced apoptosis. The anti-apoptotic effect against H 2 O 2 was similarly observed in NRK49F fibroblasts, but not in Madin-Darby canine kidney epi-thelial cells and ECV304 endothelial cells. Mesangial cells exposed to H 2 O 2 undergo apoptosis via the activa-tor protein 1 (AP-1)-dependent pathway. We found that t-RA abrogated the H 2 O 2 -induced expression of c-fos/c-jun and activation of AP-1. Furthermore, t-RA inhibited H 2 O 2 -triggered activation of c-Jun N-terminal kinase (JNK), and dominant-negative inhibition of JNK atten-uated the H 2 O 2 -induced apoptosis. These data disclosed the novel potential of retinoic acid as an inhibitor of apoptosis. The anti-apoptotic action of t-RA was as-cribed, at least in part, to dual suppression of the cell death pathway mediated by JNK and AP-1.