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.

MeSH Terms (10)

Acute Kidney Injury Animals beta Catenin Forkhead Box Protein O3 Kidney Tubules, Proximal Male Mice Mice, Transgenic Renal Insufficiency, Chronic Signal Transduction

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