Tubule-specific ablation of endogenous Β-catenin aggravates acute kidney injury in mice

Dong Zhou, Yingjian Li, Lin Lin, Lili Zhou, Peter Igarashi, Youhua Liu

Research output: Contribution to journalArticle

110 Scopus citations

Abstract

Β-Catenin is a unique intracellular protein functioning as an integral component of the cell-cell adherens complex and a principal signaling protein mediating canonical Wnt signaling. Little is known about its function in adult kidneys in the normal physiologic state or after acute kidney injury (AKI). To study this, we generated conditional knockout mice in which the Β-catenin gene was specifically disrupted in renal tubules (Ksp-Β-cat-/-). These mice were phenotypically normal with no appreciable defects in kidney morphology and function. In the absence of Β-catenin, γ-catenin functionally substituted for it in E-cadherin binding, thereby sustaining the integrity of epithelial adherens junctions in the kidneys. In AKI induced by ischemia reperfusion or folic acid, the loss of tubular Β-catenin substantially aggravated renal lesions. Compared with controls, Ksp-Β-cat-/- mice displayed higher mortality, elevated serum creatinine, and more severe morphologic injury. Consistently, apoptosis was more prevalent in kidneys of the knockout mice, which was accompanied by increased expression of p53 and Bax, and decreased phosphorylated Akt and survivin. In vitro activation of Β-catenin by Wnt1 or stabilization of Β-catenin protected tubular epithelial cells from apoptosis, activated Akt, induced survivin, and repressed p53 and Bax expression. Hence, endogenous Β-catenin is pivotal for renal tubular protection after AKI by promoting cell survival through multiple mechanisms.

Original languageEnglish (US)
Pages (from-to)537-547
Number of pages11
JournalKidney international
Volume82
Issue number5
DOIs
StatePublished - Sep 1 2012

Keywords

  • Wnt
  • acute kidney injury
  • apoptosis
  • β-catenin

ASJC Scopus subject areas

  • Nephrology

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