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

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

来源：JCI Insight, 2023, 8(2): e162060.

DOI：10.1172/jci.insight.162060

• TO-MESENCHYMAL TRANSITION
• CELL-CYCLE ARREST
• MOLECULAR-MECHANISMS
• TENASCIN-C
• PROGRESSION
• FIBROSIS
• TARGET
• IMP3

Wnt/beta-catenin is a developmental signaling pathway that plays a crucial role in driving kidney fibrosis after injury. Activation of beta-catenin is presumed to be regulated through the posttranslational protein modification. Little is known about whether beta-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 beta-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/beta-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 beta-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 beta-catenin mRNA and stabilized it against degradation. Furthermore, knockdown of IGF2BP3 in tubular cells accelerated beta-catenin mRNA degradation in vitro. These studies demonstrate that IGF2BP3 promotes beta-catenin signaling and drives kidney fibrosis, which may be mediated through stabilizing beta-catenin mRNA. Our findings uncover a previously underappreciated dimension of the complex regulation of Wnt/beta-catenin signaling and suggest a potential target for therapeutic intervention of fibrotic kidney diseases.

• 单位
  南方医科大学