We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Matrix metalloproteinase 9-dependent Notch signaling contributes to kidney fibrosis through peritubular endothelial-mesenchymal transition.
- Authors
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.; Guoping Zheng
- 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.
- Subjects
CHRONIC kidney failure; RENAL fibrosis; ENDOTHELIAL cells; MATRIX metalloproteinases; CADHERINS
- Publication
Nephrology Dialysis Transplantation, 2017, Vol 32, Issue 5, p781
- ISSN
0931-0509
- Publication type
Article
- DOI
10.1093/ndt/gfw308