Ethan Lee
Faculty Member
Last active: 8/24/2020

Tubular β-catenin and FoxO3 interactions protect in chronic kidney disease.

Nlandu-Khodo S, Osaki Y, Scarfe L, Yang H, Phillips-Mignemi M, Tonello J, Saito-Diaz K, Neelisetty S, Ivanova A, Huffstater T, McMahon R, Taketo MM, deCaestecker M, Kasinath B, Harris RC, Lee E, Gewin LS
JCI Insight. 2020 5 (10)

PMID: 32369448 · PMCID: PMC7259539 · DOI:10.1172/jci.insight.135454

The Wnt/β-catenin signaling pathway plays an important role in renal development and is reexpressed in the injured kidney and other organs. β-Catenin signaling is protective in acute kidney injury (AKI) through actions on the proximal tubule, but the current dogma is that Wnt/β-catenin signaling promotes fibrosis and development of chronic kidney disease (CKD). As the role of proximal tubular β-catenin signaling in CKD remains unclear, we genetically stabilized (i.e., activated) β-catenin specifically in murine proximal tubules. Mice with increased tubular β-catenin signaling were protected in 2 murine models of AKI to CKD progression. Oxidative stress, a common feature of CKD, reduced the conventional T cell factor/lymphoid enhancer factor-dependent β-catenin signaling and augmented FoxO3-dependent activity in proximal tubule cells in vitro and in vivo. The protective effect of proximal tubular β-catenin in renal injury required the presence of FoxO3 in vivo. Furthermore, we identified cystathionine γ-lyase as a potentially novel transcriptional target of β-catenin/FoxO3 interactions in the proximal tubule. Thus, our studies overturned the conventional dogma about β-catenin signaling and CKD by showing a protective effect of proximal tubule β-catenin in CKD and identified a potentially new transcriptional target of β-catenin/FoxO3 signaling that has therapeutic potential for CKD.

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