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Muc1 Modulates the Beta‐Catenin Protective Pathway During Ischemia‐Reperfusion Injury
Author(s) -
Albataineh Mohammad M,
Kinlough Carol L,
PastorSoler Nuria M,
Sutton Timothy A,
Poland Paul A,
Mang Henry E,
Gendler Sandra J,
Madsen Cathy S,
Singh Sucha,
Bastacky Sheldon I,
Monga Satdarshan P,
Hughey Rebecca P
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1217.5
Subject(s) - gsk3b , gsk 3 , glycogen synthase , cancer research , protein kinase b , catenin , kidney , phosphorylation , beta catenin , pi3k/akt/mtor pathway , chemistry , cyclin d1 , survivin , biology , microbiology and biotechnology , apoptosis , signal transduction , endocrinology , wnt signaling pathway , cell cycle , biochemistry
The 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 1 (Muc1) 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. 2015 Am. J. Physiol. Renal Physiol. 308, F1452‐F1462). We asked if Muc1 regulates the β‐catenin protective pathway during IRI as published data indicate that (i) β‐catenin is found in co‐immunoprecipitates with human MUC1 in extracts of both cultured cells and tissues, (ii) β‐catenin nuclear targeting is MUC1‐dependent in cultured human cells, and (iii) MUC1 prevents β‐catenin phosphorylation by glycogen synthase kinase 3β (GSK3b) and thereby β‐catenin degradation. Using our same mouse model of IRI, and by using immunohistochemistry and immunoblotting of kidney tissue, we found that levels of active GSK3β were significantly lower in kidneys of control mice compared to Muc1 KO mice. Consequently, β‐catenin was significantly increased at 24 and 72 h 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. In accord with these data, we also found downstream induction of β‐catenin pro‐survival factors (activated Akt, survivin, transcription factor TCF4 and its downstream target cyclin D1) and repression of pro‐apoptotic 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 AKI proceeds by enhancing both the HIF‐1 and β‐catenin protective pathways. Support or Funding Information This work was supported by National Institutes of Health (NIH) Grants DK‐099345 (to T. A. Sutton), DK‐084184 (to N. M. Pastor‐Soler), CA‐64389 (to S. J. Gendler), DK‐62277, DK‐100287, and DK‐095498 (to S. P. Monga), DK‐097889 (to M. M. Al‐bataineh), DK107632, DK‐079307 (Pilot Project) and Samuel and Emma Winters Foundation grant (to R. P. Hughey), and P30‐DK079307 (to the Microscopy Core N. M. Pastor‐Soler and S. Bastacky).