1. Matrix metalloproteinase 9-dependent Notch signaling contributes to kidney fibrosis through peritubular endothelial-mesenchymal transition.
- Author
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Ye Zhao, Xi Qiao, Thian Kui Tan, Hong Zhao, Yun Zhang, Lixin Liu, Jianlin Zhang, Lihua Wang, Qi Cao, Yiping Wang, Ya Wang, Yuan Min Wang, Lee, Vincent W. S., Alexander, Stephen I., Harris, David C. H., and Guoping Zheng
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CHRONIC kidney failure , *RENAL fibrosis , *ENDOTHELIAL cells , *MATRIX metalloproteinases , *CADHERINS - Abstract
Background: Endothelial cells are known to contribute to kidney fibrosis via endothelial-mesenchymal transition (EndoMT). Matrix metalloproteinase 9 (MMP-9) is known to be profibrotic. However, whether MMP-9 contributes to kidney fibrosis via EndoMT is unknown. Methods: Primary mouse renal peritubular endothelial cells (MRPECs) were isolated and treated by recombinant human transforming growth factor beta 1 (rhTGF-β1) with or without MMP-9 inhibitor or by recombinant human MMP-9 (rhMMP- 9) alone. Kidney fibrosis was induced by unilateral ureteral obstruction (UUO) in MMP-9 knockout (KO) and wide-type (WT) control mice. The effects of MMP-9 on EndoMT of MRPECs and kidney fibrosis were examined. Results: We showed that MRPECs underwent EndoMT after rhTGF-β1 treatment or in UUO kidney as evidenced by decreased expression of endothelial markers, vascular endothelial cadherin (VE-cadherin) and CD31, and increased levels of mesenchymal markers, a-smooth muscle actin (a-SMA) and vimentin. The expression of fibrosis markers was also upregulated significantly after rhTGF-β1 treatment in MRPECs. The EndoMT and fibrosis markers were significantly less in rhTGF-β1-treated MMP-9 KO MRPECs, whereas MMP-9 alone was sufficient to induce EndoMT in MRPECs. UUO kidney ofMMP-9 KO mice showed significantly less interstitial fibrosis and EndoMT in MRPECs. Notch signaling shown by Notch intracellular domain (NICD) was increased, while Notch-1 was decreased in rhTGF-β1-treated MRPECs of MMP-9WT but notMMP-9 KO mice. Inhibition ofMMP-9 or Notch signaling prevented rhTGF-β1- or rhMMP-9-induced a-SMA and NICD upregulation in MRPECs. UUO kidney of MMP-9 KOmice had less staining of Notch signaling transcription factor Hey-1 in VE-cadherin-positive MRPECs than WT controls. Conclusions: Our results demonstrate that MMP-9-dependent Notch signaling plays an important role in kidney fibrosis through EndoMT ofMRPECs. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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