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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 4

Inhibiting FoxO3 in PT cells increases while ICG-001 reduces AA-induced apoptosis.

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Inhibiting FoxO3 in PT cells increases while ICG-001 reduces AA-induced ...
(A) We effectively reduced FoxO3 expression in PT cells by immunoblots using siRNA. (B) PT cells treated with Foxo3 or scramble siRNA were treated with AA, and apoptosis was measured by cleaved caspase-3 on immunoblots with GAPDH as loading control. (C) The results of 3 independent studies were quantified by ImageJ. (D) PT cells were treated ± AA (30 μM for 7 days) and ICG-001 to inhibit β-catenin/TCF/LEF for the last 4 days and then lysates blotted for cleaved caspase-3 and GAPDH for loading. (E) Three experiments with AA + ICG-001 or DMSO (diluent control) are quantified, and the data were normalized to AA + DMSO. Student’s t test was used for statistical comparisons with *P < 0.05 and **P < 0.01. GAPDH, glyceraldehyde 3, phosphate dehydrogenase.

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