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Insulin-like growth factor 2 mRNA-binding protein 3 promotes kidney injury by regulating β-catenin signaling
Dongyan Song, … , Haiyan Fu, Youhua Liu
Dongyan Song, … , Haiyan Fu, Youhua Liu
Published December 15, 2022
Citation Information: JCI Insight. 2023;8(2):e162060. https://doi.org/10.1172/jci.insight.162060.
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Research Article Nephrology

Insulin-like growth factor 2 mRNA-binding protein 3 promotes kidney injury by regulating β-catenin signaling

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Abstract

Wnt/β-catenin is a developmental signaling pathway that plays a crucial role in driving kidney fibrosis after injury. Activation of β-catenin is presumed to be regulated through the posttranslational protein modification. Little is known about whether β-catenin is also subjected to regulation at the posttranscriptional mRNA level. Here, we report that insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) plays a pivotal role in regulating β-catenin. IGF2BP3 was upregulated in renal tubular epithelium of various animal models and patients with chronic kidney disease. IGF2BP3 not only was a direct downstream target of Wnt/β-catenin but also was obligatory for transducing Wnt signal. In vitro, overexpression of IGF2BP3 in kidney tubular cells induced fibrotic responses, whereas knockdown of endogenous IGF2BP3 prevented the expression of injury and fibrosis markers in tubular cells after Wnt3a stimulation. In vivo, exogenous IGF2BP3 promoted β-catenin activation and aggravated kidney fibrosis, while knockdown of IGF2BP3 ameliorated renal fibrotic lesions after obstructive injury. RNA immunoprecipitation and mRNA stability assays revealed that IGF2BP3 directly bound to β-catenin mRNA and stabilized it against degradation. Furthermore, knockdown of IGF2BP3 in tubular cells accelerated β-catenin mRNA degradation in vitro. These studies demonstrate that IGF2BP3 promotes β-catenin signaling and drives kidney fibrosis, which may be mediated through stabilizing β-catenin mRNA. Our findings uncover a previously underappreciated dimension of the complex regulation of Wnt/β-catenin signaling and suggest a potential target for therapeutic intervention of fibrotic kidney diseases.

Authors

Dongyan Song, Jingyue Shang, Yinyi Long, Menghua Zhong, Li Li, Jiongcheng Chen, Yadie Xiang, Huishi Tan, Haili Zhu, Xue Hong, Fan Fan Hou, Haiyan Fu, Youhua Liu

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Figure 7

Knockdown of IGF2BP3 ameliorates renal fibrosis and inhibits β-catenin signaling activation after UUO.

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Knockdown of IGF2BP3 ameliorates renal fibrosis and inhibits β-catenin s...
(A) Experimental design. The green arrow indicates the timing of injecting Ctrl-shR or IGF2BP3-shR. The black arrow indicates the timing of UUO. (B and C) Representative Western blot (B) and quantitative data (C) show the expression of IGF2BP3 protein in different groups as indicated. ***P < 0.001 versus the sham group; †††P < 0.001 versus the UUO injected with Ctrl-shR group (n = 5, ANOVA with Student-Newman-Keuls test). (D) Micrographs show collagen deposition at 7 days after UUO in different groups. Arrows indicate positive staining. Scale bar, 50 μm. (E) Graphical presentation of renal fibrotic lesions in different groups. ***P < 0.001 versus the sham group; †P < 0.05 versus the UUO injected with Ctrl-shR group (n = 5, ANOVA with Student-Newman-Keuls test). (F) Representative Western blots show the expression of E-cadherin, vimentin, fibronectin, α-SMA, and collagen I protein in different groups as indicated. (G) Micrographs show E-cadherin, vimentin, fibronectin, α-SMA, and β-catenin at 7 days after UUO in different groups. Arrows indicate positive staining. Scale bar, 50 μm. (H) Representative Western blots show the expression of β-catenin, active β-catenin, PAI-1, MMP-7, Snail1, p-H3, and p16INK4A proteins in different groups as indicated.

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