Downregulation of Fas activity rescues early onset of diabetes in c-Kit(Wv/+) mice

作者：Feng Zhi Chao; Riopel Matthew; Li Jinming; Donnelly Lisa; Wang Rennian^*

来源：American Journal of Physiology - Endocrinology And Metabolism, 2013, 304(6): E557-E565.

DOI：10.1152/ajpendo.00453.2012

• c-Kit
• Fas
• beta-cell apoptosis
• insulin secretion
• diabetes

Feng Z, Riopel M, Li J, Donnelly L, RW. Downregulation of Fas activity rescues early onset of diabetes in c-Kit(Wv/+) mice. Am J Physiol Endocrinol Metab 67: E557-E565, 2013. First published December 26, 2012; doi:10.1152/ajpendo.00453.2012.-c-Kit and its ligand stem cell factor (SCF) are important for beta-cell survival and maturation; meanwhile, interactions between the Fas receptor (Fas) and Fas ligand are capable of triggering beta-cell apoptosis. Disruption of c-Kit signaling leads to severe loss of beta-cell mass and function with upregulation of Fas expression in c-Kit(Wv/+) mouse islets, suggesting that there is a critical balance between c-Kit and Fas activation in beta-cells. In the present study, we investigated the interrelationship between c-Kit and Fas activation that mediates beta-cell survival and function. We generated double mutant, c-Kit(Wv/+); Fas(lpr/lpr) (Wv(-/-)), mice to study the physiological and functional role of Fas with respect to beta-cell function in c-Kit(Wv/+) mice. Isolated islets from these mice and the INS-1 cell line were used. We observed that islets in c-Kit(Wv/+) mice showed a significant increase in beta-cell apoptosis along with upregulated p53 and Fas expression. These results were verified in vitro in INS-1 cells treated with SCF or c-Kit siRNA combined with a p53 inhibitor and Fas siRNA. In vivo, Wv(-/-) mice displayed improved beta-cell function, with significantly enhanced insulin secretion and increased beta-cell mass and proliferation compared with Wv(+/+) mice. This improvement was associated with downregulation of the Fas-mediated caspase-dependent apoptotic pathway and upregulation of the cFlip/NF-kappa B pathway. These findings demonstrate that a balance between the c-Kit and Fas signaling pathways is critical in the regulation of beta-cell survival and function.

• 出版日期2013-3