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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Kidney Injury / chemically induced
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Acute Kidney Injury / genetics
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Acute Kidney Injury / metabolism*
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Acute Kidney Injury / pathology
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Adherens Junctions / metabolism
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Animals
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Apoptosis
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Cadherins / metabolism
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Cell Line
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Creatinine / blood
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Disease Models, Animal
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Epithelial Cells / metabolism
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Folic Acid
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Genotype
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Humans
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / metabolism
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Kidney Tubules / metabolism*
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Kidney Tubules / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Phenotype
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Phosphorylation
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Proto-Oncogene Proteins c-akt / metabolism
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Reperfusion Injury / etiology
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Reperfusion Injury / genetics
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Reperfusion Injury / metabolism*
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Reperfusion Injury / pathology
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Survivin
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Time Factors
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Transfection
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Tumor Suppressor Protein p53 / metabolism
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Wnt1 Protein / genetics
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Wnt1 Protein / metabolism
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bcl-2-Associated X Protein / metabolism
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beta Catenin / deficiency*
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beta Catenin / genetics
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beta Catenin / metabolism
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gamma Catenin / metabolism
Substances
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BAX protein, human
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BIRC5 protein, human
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Bax protein, mouse
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Birc5 protein, mouse
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CTNNB1 protein, human
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CTNNB1 protein, mouse
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Cadherins
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Inhibitor of Apoptosis Proteins
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Jup protein, mouse
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Repressor Proteins
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Survivin
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TP53 protein, human
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Tumor Suppressor Protein p53
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Wnt1 Protein
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bcl-2-Associated X Protein
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beta Catenin
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gamma Catenin
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Folic Acid
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Creatinine
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Proto-Oncogene Proteins c-akt