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β-Catenin Promotes Survival of Renal Epithelial Cells by Inhibiting Bax

Zhiyong Wang^*, Andrea Havasi^*, Jonathan M. Gall^*, Haiping Mao, John H. Schwartz^* and Steven C. Borkan^*

*Renal Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts; and
First Affiliated Hospital, Zhongshan University, Guangzhou, People's Republic of China

Correspondence: Dr. Steven C. Borkan, Evans Biomedical Research Center, Renal Section, Room #546, 650 Albany Street, Boston, MA 02118-2518. Phone: 617-638-7330; Fax: 617-638-7326; E-mail: sborkan{at}bu.edu

Received for publication March 6, 2009. Accepted for publication April 17, 2009.

Ischemia activates Bax, a proapoptotic BCL2 protein, as well as the prosurvival β-catenin/Wnt signaling pathway. To test the hypothesis that β-catenin/Wnt signaling regulates Bax-mediated apoptosis after induction of metabolic stress, which occurs during renal ischemia, we infected immortalized and primary proximal tubular epithelial cells with adenovirus to express either constitutively active or dominant negative β-catenin constructs. Constitutively active β-catenin significantly decreased apoptosis and improved cell survival after metabolic stress. Furthermore, active β-catenin decreased Bax activation, oligomerization, and translocation to mitochondria, and reduced both organelle membrane injury and apoptosis. Dominant negative β-catenin had the opposite effects. Because Akt regulates Bax, we examined the effects of the β-catenin mutants on Akt expression and activation. Constitutively active β-catenin increased Akt-1 expression and activation before and after stress, and treatment with a phosphatidylinositol-3 kinase inhibitor antagonized the protective effects of β-catenin on Akt activation, Bax inhibition, and cell survival. In addition, β-catenin significantly increased the rate of phosphorylation at Bax serine¹⁸⁴, an Akt-specific target. Taken together, these results suggest that β-catenin/Wnt signaling promotes survival of renal epithelial cells after metabolic stress, in part by inhibiting Bax in a phosphatidylinositol-3 kinase/Akt-dependent manner.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673