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

Abstract

Wnt/β-catenin is a developmental signaling that plays a crucial role in driving kidney fibrosis after injury. Activation of β-catenin is presumed to be regulated through the post-translational 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 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 assay revealed that IGF2BP3 directly bound to β-catenin mRNA and stabilized it from 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 new dimension of the complex regulation of Wnt/β-catenin signaling and suggest a potential target for therapeutic intervention of fibrotic kidney diseases.

Differential expression and clinical significance of IGF2BP3 in peritoneal dialysate of patients with varying duration of peritoneal dialysis

“…Recent studies suggest that IGF2BP3 is a downstream target of Wnt/β‐catenin signaling and plays a key role in renal fibrosis. Knockdown of IGF2BP3 can improve renal fibrosis and inhibit the activation of β‐catenin signaling 13 . Guo et al.…”

“…Knockdown of IGF2BP3 can improve renal fibrosis and inhibit the activation of βcatenin signaling. 13 Guo et al found that the expression of many Wnt family members and βcatenin increases in a high-glucose environment or the PD effluent of long-term dialysis patients, also accompanied by increased FN expression. 22 This suggests that IGF2BP3 may play an important role in PD-related PF via the Wnt/β-catenin signaling pathway.…”

“…Recent studies have reported elevated levels of IGF2BP3 in different types of cancers, including colon and gastric cancer, and have established its links with angiogenesis, vascular endothelial growth factor (VEGF), and specific profibrotic factors 9–12 . Existing literature also suggests that IGF2BP3 contributes to the progression of liver and renal fibrosis 13,14 . However, its expression and role in peritoneal fibrosis related to PD have yet to be examined.…”

Genetic and pharmacological inhibition of METTL3 alleviates renal fibrosis by reducing EVL m6A modification through an IGF2BP2‐dependent mechanism

“…[4][5][6] Moreover, research has also focused on the nonnegligible effects of the Wnt/β-catenin and Hedgehog pathways in renal fibrosis. 7,8 Such findings have accelerated the advancement of mechanistic exploration and therapeutic translational research in renal fibrosis. Nevertheless, the complicated mechanisms of renal fibrosis remain unclear, and more intensive research efforts are urgently needed.…”

“…Several studies have explored the dual function of transforming growth factor‐β (TGF‐β)/Smad signalling in the course of renal fibrosis 4–6 . Moreover, research has also focused on the nonnegligible effects of the Wnt/β‐catenin and Hedgehog pathways in renal fibrosis 7,8 . Such findings have accelerated the advancement of mechanistic exploration and therapeutic translational research in renal fibrosis.…”