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

Mohammad M. Al-Bataineh, Carol L. Kinlough, Paul A. Poland, Núria M. Pastor-Soler, Timothy A. Sutton, Henry E. Mang, Sheldon I. Bastacky, Sandra J. Gendler, Cathy S. Madsen, Sucha Singh, Satdarshan P. Monga, Rebecca P. Hughey

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

The hypoxia-inducible factor (HIF)-1 and β-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-1α, 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 β-catenin protective pathway during IRI as 1)β-catenin nuclear targeting is MUC1 dependent in cultured human cells, 2)β-catenin is found in coimmunoprecipitates with human MUC1 in extracts of both cultured cells and tissues, and 3) MUC1 prevents β-catenin phosphorylation by glycogen synthase kinase (GSK)3 and thereby-catenin degradation. Using the same mouse model of IRI, we found that levels of active GSK3 were significantly lower in kidneys of control mice compared with Muc1 knockout (KO) mice. Consequently, β-catenin was significantly upregulated at 24 and 72 h of recovery and appeared in the nuclear fraction at 72 h in control mouse kidneys. Both β-catenin induction and nuclear targeting were absent in Muc1 KO mice. We also found downstream induction of β-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 β-catenin protective pathways.

Original languageEnglish (US)
Pages (from-to)F569-F579
JournalAmerican Journal of Physiology - Renal Physiology
Volume310
Issue number6
DOIs
StatePublished - Mar 15 2016

Keywords

  • Acute kidney injury
  • Ischemia
  • Mucin 1
  • β-catenin

ASJC Scopus subject areas

  • Physiology
  • Urology

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    Al-Bataineh, M. M., Kinlough, C. L., Poland, P. A., Pastor-Soler, N. M., Sutton, T. A., Mang, H. E., Bastacky, S. I., Gendler, S. J., Madsen, C. S., Singh, S., Monga, S. P., & Hughey, R. P. (2016). Muc1 enhances the β-catenin protective pathway during ischemia-reperfusion injury. American Journal of Physiology - Renal Physiology, 310(6), F569-F579. https://doi.org/10.1152/ajprenal.00520.2015