Muc1 enhances the beta-catenin protective pathway during ischemia-reperfusion injury

作者：Al bataineh Mohammad M; Kinlough Carol L; Poland Paul A; Pastor Soler Nuria M; Sutton Timothy A; Mang Henry E; Bastacky Sheldon I; Gendler Sandra J; Madsen Cathy S; Singh Sucha; Monga Satdarshan P; Hughey Rebecca P

来源：American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 2016, 310(6): F569-F579.

DOI：10.1152/ajprenal.00520.2015

• acute kidney injury
• ischemia
• mucin 1
• beta-catenin

The hypoxia-inducible factor (HIF)-1 and beta-catenin protective pathways represent the two most significant cellular responses that are activated in response to acute kidney injury. We previously reported that murine mucin (Muc) 1 protects kidney function and morphology in a mouse model of ischemia-reperfusion injury (IRI) by stabilizing HIF-1 alpha, enhancing HIF-1 downstream signaling, and thereby preventing metabolic stress (Pastor-Soler et al. Muc1 is protective during kidney ischemia-reperfusion injury. Am J Physiol Renal Physiol 308: F1452-F1462, 2015). We asked if Muc1 regulates the beta-catenin protective pathway during IRI as 1) beta-catenin nuclear targeting is MUC1 dependent in cultured human cells, 2) beta-catenin is found in coimmunoprecipitates with human MUC1 in extracts of both cultured cells and tissues, and 3) MUC1 prevents beta-catenin phosphorylation by glycogen synthase kinase (GSK)3 beta and thereby beta-catenin degradation. Using the same mouse model of IRI, we found that levels of active GSK3 beta were significantly lower in kidneys of control mice compared with Muc1 knockout (KO) mice. Consequently, beta-catenin was significantly up-regulated at 24 and 72 h of recovery and appeared in the nuclear fraction at 72 h in control mouse kidneys. Both beta-catenin induction and nuclear targeting were absent in Muc1 KO mice. We also found downstream induction of beta-catenin prosurvival factors (activated Akt, survivin, transcription factor T cell factor 4 (TCF4), and its downstream target cyclin D1) and repression of proapoptotic factors (p53, active Bax, and cleaved caspase-3) in control mouse kidneys that were absent or aberrant in kidneys of Muc1 KO mice. Altogether, the data clearly indicate that Muc1 protection during acute kidney injury proceeds by enhancing both the HIF-1 and beta-catenin protective pathways.

• 出版日期2016-3-15