title: Muc1 enhances the β-catenin protective pathway during ischemia-reperfusion injury.
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.
authors.affiliation: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Al-Bataineh
authors.affiliation: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Carol L
authors.initials: CL
authors.lastname: Kinlough
authors.affiliation: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Paul A
authors.initials: PA
authors.lastname: Poland
authors.affiliation: 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;
authors.forename: Núria M
authors.initials: NM
authors.lastname: Pastor-Soler
authors.affiliation: Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Sutton
authors.affiliation: Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
authors.forename: Henry E
authors.initials: HE
authors.lastname: Mang
authors.affiliation: Division of Anatomic Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Sheldon I
authors.initials: SI
authors.lastname: Bastacky
authors.affiliation: 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.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Gendler
authors.affiliation: Division of Anatomic Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Cathy S
authors.initials: CS
authors.lastname: Madsen
authors.affiliation: Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Sucha
authors.initials: S
authors.lastname: Singh
authors.affiliation: Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Satdarshan P
authors.initials: SP
authors.lastname: Monga
authors.affiliation: 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.
authors.forename: Rebecca P
authors.initials: RP
authors.lastname: Hughey
mesh_terms: D000818:Animals; D017209:Apoptosis; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018396:Mucin-1 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D000077022:Survivin; D000073940:Transcription Factor 4; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C117749:Birc5 protein, mouse; C495267:CTNNB1 protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051034:Inhibitor of Apoptosis Proteins; D018396:Mucin-1; D012097:Repressor Proteins; D000077022:Survivin; C090743:Tcf4 protein, mouse; D000073940:Transcription Factor 4; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051176:beta Catenin; C577056:muc1 protein, mouse; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt
keywords: acute kidney injury; ischemia; mucin 1; β-catenin