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  • Title: PAX2 may induce ADAM10 expression in renal tubular epithelial cells and contribute to epithelial-to-mesenchymal transition.
    Author: Hou L, Du Y, Zhao C, Wu Y.
    Journal: Int Urol Nephrol; 2018 Sep; 50(9):1729-1741. PubMed ID: 30117015.
    Abstract:
    PURPOSE: We sought to investigate the role of PAX2 in renal epithelial-to-mesenchymal transition (EMT), examining the influence of PAX2 on ADAM10 expression during renal EMT and ADAM10 expression in fibrotic kidneys. METHODS: A rat renal tubular epithelial cell line, NRK52E, was transfected with lentivirus carrying PAX2, and E-cadherin and α-SMA expressions were measured. The influence of PAX2 on ADAM10 promoter activity was evaluated using chromatin immunoprecipitation (CHIP) and dual-luciferase reporter assay. We also treated NRK52E with ADAM10-specific over-expression vector and inhibitors and measured E-cadherin and α-SMA expression. In vivo, Wistar rats (n = 36) were subjected to unilateral ureteral obstruction (UUO) (n = 18) or sham surgery (n = 18), with tissues from post-operative day 3, 7, and 14 days examined, and PAX2/ADAM10 activity measured. ADAM10 expression was also assessed in kidneys from patients with chronic kidney disease (CKD). RESULTS: In NRK52E overexpressing PAX2, ADAM10 and α-SMA levels were increased, while E-cadherin levels were decreased. CHIP and dual-luciferase reporter assay showed that PAX2 directly bound to a specific site within the ADAM10 promoter, and over-expression of PAX2 significantly activated ADAM10 transcription. NRK52E with ADAM10 over-expression also significantly decreased E-cadherin and increased α-SMA levels. In the fibrotic kidneys of rats with UUO, E-cadherin levels were increased and α-SMA levels were decreased, and expression of PAX2 and ADAM10 increased. ADAM10 expression also elevated in the renal tissues of CKD patients. CONCLUSIONS: PAX2 directly increased expression of ADAM10, the presence of which contributed to EMT in renal tubular epithelia and hence plays an important role in renal fibrosis.
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