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

beta-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 beta-catenin gene was specifically disrupted in renal tubules (Ksp-beta-cat-/-). These mice were phenotypically normal with no appreciable defects in kidney morphology and function. In the absence of beta-catenin, gamma-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 beta-catenin substantially aggravated renal lesions. Compared with controls, Ksp-beta-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 beta-catenin by Wnt1 or stabilization of beta-catenin protected tubular epithelial cells from apoptosis, activated Akt, induced survivin, and repressed p53 and Bax expression. Hence, endogenous beta-catenin is pivotal for renal tubular protection after AKI by promoting cell survival through multiple mechanisms.