Matrix metalloproteinase 9 induces endothelial-mesenchymal transition via Notch activation in human kidney glomerular endothelial cells. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Zhao, Ye; Qiao, Xi; Wang, Lihua; Tan, Tian; Zhao, Hong; Zhang, Yun; Zhang, Jianlin; Rao, Padmashree; Cao, Qi; Wang, Yiping; Wang, Ya; Wang, Yuan; Lee, Vincent; Alexander, Stephen; Harris, David; Zheng, Guoping
• Is Part Of: BMC cell biology. Volume 17:Issue 1(2016)
• Page Start: 1
• Page End: 11
• Publication Date: 2016-12
• Subjects: Matrix metalloproteinase 9 -- Endothelial-mesenchymal transition -- Human glomerular endothelial cells -- TGF-β1 -- Notch; Cytology -- Periodicals; 571.605
• DOI: 10.1186/s12860-016-0101-0
• Languages: English
• ISSNs: 1471-2121

Abstract

Abstract Background Endothelial-mesenchymal transition (EndoMT) is a major source of myofibroblast formation in kidney fibrosis. Our previous study showed a profibrotic role for matrix metalloproteinase 9 (MMP-9) in kidney fibrosis via induction of epithelial-mesenchymal transition (EMT). Inhibition of MMP-9 activity reduced kidney fibrosis in murine unilateral ureteral obstruction. This study investigated whether MMP-9 also plays a role in EndoMT in human glomerular endothelial cells. Results TGF-β1 (10 or 20 ng/ml) induced EndoMT in HKGECs as shown by morphological changes. In addition, VE-cadherin and CD31 were significantly downregulated, whereas α-SMA, vimentin, and N-cadherin were upregulated. RT-PCR revealed that Snail, a known inducer of EMT, was upregulated. The MMP inhibitor GM6001 abrogated TGF-β1-induced EndoMT. Zymography indicated that MMP-9 was also upregulated in TGF-β1-treated HKGECs. Recombinant MMP-9 (2 μg/ml) induced EndoMT in HKGECs via Notch signaling, as evidenced by increased formation of the Notch intracellular domain (NICD) and decreased Notch 1. Inhibition of MMP-9 activity by its inhibitor showed a dose-dependent response in preventing TGF-β1-induced α-SMA and NICD in HKGECs, whereas inhibition of Notch signaling by γ-secretase inhibitor (GSI) blocked rMMP-9-induced EndoMT. Conclusions Taken together, our results demonstrate that MMP-9 plays an important role in TGF-β1-induced EndoMT via upregulation of Notch signaling in HKGECs.