CUX1 promotes epithelial-mesenchymal transition (EMT) in renal fibrosis of UUO model by targeting MMP7

Epithelial-to-mesenchymal transition (EMT) displays a critical role in the development of renal fibrosis, an important pathological process of chronic kidney disease (CKD). Transcription factor Cut-like homeobox 1 (CUX1) has shown profound effects on several kidney diseases. However, its role in CKD has not been understood yet. In this study, unilateral ureteric obstruction (UUO) surgery was performed on male C57BL/6 mice to simulate CKD in vivo. Renal fibrosis was further induced in human proximal tubular epithelial cell (HK-2) by TGF-β1 stimulation. CUX1 and MMP7 were found to be over-expressed in renal tissue of UUO mice. Renal functional analyses and histological assessment indicated that CUX1 knockdown alleviated renal injury in UUO mice. Mitochondrial dysfunction was determined in UUO group and improved after CUX1 silencing. Besides, CUX1 knockdown suppressed EMT in UUO mice and TGF-β1 treated HK-2 cells, as evidenced by reduced expressions of α-SMA, vimentin, fibronectin and augmented abundance of E-cadherin. Furthermore, CUX1 knockdown decreased MMP7 expression by targeting at its promoter region. MMP7 was responsible for the inhibitory effect of CUX1 knockdown on EMT in HK-2 cells. In summary, our findings suggest that CUX1 promotes EMT in CKD by targeting MMP7, and highlight the crucial role of CUX1 in CKD pathogenesis.