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Tubular β-catenin and FoxO3 interactions protect in chronic kidney disease
Stellor Nlandu-Khodo, … , Ethan Lee, Leslie S. Gewin
Stellor Nlandu-Khodo, … , Ethan Lee, Leslie S. Gewin
Published May 5, 2020
Citation Information: JCI Insight. 2020;5(10):e135454. https://doi.org/10.1172/jci.insight.135454.
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Research Article Cell biology Nephrology

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

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Abstract

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.

Authors

Stellor Nlandu-Khodo, Yosuke Osaki, Lauren Scarfe, Haichun Yang, Melanie Phillips-Mignemi, Jane Tonello, Kenyi Saito-Diaz, Surekha Neelisetty, Alla Ivanova, Tessa Huffstater, Robert McMahon, M. Mark Taketo, Mark deCaestecker, Balakuntalam Kasinath, Raymond C. Harris, Ethan Lee, Leslie S. Gewin

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Figure 7

Injured mice with β-catenin stabilized in the PT have increased protein expression of CSE.

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Injured mice with β-catenin stabilized in the PT have increased protein ...
(A) Cortical lysates from Ggt-Cre Ctnnb1ex3fl/fl mice and floxed controls 6 weeks after AA treatment were immunoblotted for CSE with α-tubulin for loading control. (B) ImageJ was used to quantify the differences in CSE protein expression. (C) Immunohistochemistry for CSE was performed on uninjured and AAN (6 weeks) kidneys. (D) Cth transcripts were measured by qPCR in renal cortical tissue from uninjured and 6-week AA-treated mice. (E) Immunoblots from cortical lysates of mice injured by AA and stained for CSE and α-tubulin for loading control. Student’s t test was used to compare 2 groups of samples with *P < 0.05 and **P < 0.01. Scale bar: 50 μm.

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