TRIM46 upregulates Wnt/β-catenin signaling by inhibiting Axin1 to mediate hypoxia-induced epithelial-mesenchymal transition in HK2 cells.

Hypoxia can cause Epithelial-mesenchymal transition (EMT) in renal tubular cells, and in turn, renal fibrosis. We tested the expression of TRIM46, a member of tripartite motif-containing (TRIM) family proteins, and mesenchymal markers under hypoxia. Our results showed that hypoxia significantly enhanced expression of TRIM46 in HK2 human renal proximal tubular epithelial cells. Our data further showed that hypoxia led to upregulated expression of mesenchymal markers including α-smooth muscle actin, vimentin, and Snail, and downregulated expression of epithelial marker E-cadherin, coupled with an increased abundance of nuclear β-catenin. However, such effects were reversed when TRIM46 expression was knocked down. TRIM46 overexpression had similar effects as hypoxia exposure, and such effects were reversed when cells were treated with XAV-939, a selective inhibitor for β-catenin. Furthermore, we found that TRIM46 promoted ubiquitination and proteasomal degradation of Axin1 protein, a robust negative regulator of Wnt/β-catenin signaling activity. Finally, increased TRIM46 coupled with decreased Axin1 was observed in a rat renal fibrosis model. These data suggest a novel mechanism contributing to EMT that mediates hypoxia-induced renal fibrosis. Our results suggest that selectively inhibiting this pathway that activates fibrosis in human kidney may lead to development of a novel therapeutic approach for managing this disease.