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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 1

IGF2BP3 is upregulated in renal tubular epithelium in various models of CKD.

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IGF2BP3 is upregulated in renal tubular epithelium in various models of ...
(A and B) Western blotting and quantitative determination of IGF2BP3 protein in the kidney at 7 days after UUO. Kidney homogenates after sham and UUO treatment were subjected to Western blotting using anti-IGF2BP3 antibody. **P < 0.01 versus sham (n = 4, t test). (C and D) Western blot analyses of renal expression of IGF2BP3 in IRI. IGF2BP3 expression was assessed in the kidneys at 11 days after IRI. ***P < 0.001 versus sham (n = 4, t test). (E and F) Western blot analyses of renal expression of IGF2BP3 in ADR. IGF2BP3 expression was assessed in the kidneys at 2 weeks after ADR. **P < 0.01 versus sham (n = 4, t test). (G and H) Western blot analyses of renal expression of IGF2BP3 after Ang II infusion. IGF2BP3 expression was assessed in the kidneys at 4 weeks after Ang II infusion. *P < 0.05 versus sham (n = 4, t test). (I) Representative micrographs show renal expression and localization of IGF2BP3 protein in various animal models of CKD. IGF2BP3 was detected by immunohistochemical staining. Arrows indicates positive staining. Scale bar, 50 μm. (J) Western blots showed IGF2BP3 and active β-catenin distribution in cytosolic and nuclear fractions at 11 days after IRI. α-Tubulin and TATA-binding protein (TBP) were used to normalize cytosolic and nuclear fractions. (K–M) qRT-PCR showed renal mRNA levels of IGF2BP3 after UUO (K), IRI (L), and ADR (M), respectively. *P < 0.05, ***P < 0.001 versus sham (n = 4, t test). Numbers to left of blots indicate kDa.

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