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.