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Am J Physiol Renal Physiol. 2016 Mar 15;310(6):F569-79. doi: 10.1152/ajprenal.00520.2015. Epub 2016 Jan 6.

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

Author information

1
Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
2
Division of Nephrology and Hypertension, Department of Medicine, University of Southern California/UKRO Kidney Research Center, Keck School of Medicine of the University of Southern California, Los Angeles, California;
3
Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
4
Division of Anatomic Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
5
Department of Immunology and Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Comprehensive Cancer Center, Mayo Clinic in Arizona, Scottsdale, Arizona.
6
Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
7
Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania hugheyr@pitt.edu.

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)3β and thereby β-catenin degradation. Using the same mouse model of IRI, we found that levels of active GSK3β 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.

KEYWORDS:

acute kidney injury; ischemia; mucin 1; β-catenin

PMID:
26739894
PMCID:
PMC4796271
DOI:
10.1152/ajprenal.00520.2015
[Indexed for MEDLINE]
Free PMC Article

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