ACVR1 mediates renal tubular EMT in kidney fibrosis via AKT activation

Abstract

Tubulointerstitial fibrosis in the kidneys is a chronic and progressive process. Although studies suggested that tubular epithelial-mesenchymal transition (EMT) plays a key role in the development of kidney fibrosis, whether ACVR1, a member of the TGFβ superfamily, is involved in the EMT needs to be illustrated.

Using bioinformatics analysis of bulk-seq data (GSE23338 and GSE168876), we found that TGF-β1 perhaps activated the PI3K/AKT signaling pathway and induced the mRNA expression of ACVR1, fibronectin, and Collagen I in HK-2 cells (human renal tubular epithelial cell line). Furthermore, qPCR and western blotting results confirmed the high expressions of ACVR1 and EMT markers in TGFβ-induced HK-2 cells. Similar results were also found in the UUO mouse model. Besides, different time-point immunofluorescent staining indicated a positive correlation between the expression of the ACVR1 and EMT marker vimentin in TGF-β1-induced HK-2 cells. Consequently, knockdown ACVR1 effectively inhibited the expression of TGF-β1-induced EMT markers and AKT phosphorylation in HK-2 cells. Moreover, treatment of HK-2 cells with MK2206 (an allosteric inhibitor of AKT) decreased the activation of AKT and the expression of α-SMA while treatment of cells with SC79 (a AKT activator) enhanced the expression of α-SMA.

These findings suggest that ACVR1 regulated the EMT of renal tubular epithelial cells through activation of the AKT signaling pathway and that ACVR1 could be considered novel therapeutic targets for renal fibrosis.