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2017 ; 32
(5
): 781-791
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Matrix metalloproteinase 9-dependent Notch signaling contributes to kidney
fibrosis through peritubular endothelial-mesenchymal transition
#MMPMID27566305
Zhao Y
; Qiao X
; Tan TK
; Zhao H
; Zhang Y
; Liu L
; Zhang J
; Wang L
; Cao Q
; Wang Y
; Wang Y
; Wang YM
; Lee VWS
; Alexander SI
; Harris DCH
; Zheng G
Nephrol Dial Transplant
2017[May]; 32
(5
): 781-791
PMID27566305
show ga
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-?1) 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-?1 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,
?-smooth muscle actin (?-SMA) and vimentin. The expression of fibrosis markers
was also up-regulated significantly after rhTGF-?1 treatment in MRPECs. The
EndoMT and fibrosis markers were significantly less in rhTGF-?1-treated MMP-9 KO
MRPECs, whereas MMP-9 alone was sufficient to induce EndoMT in MRPECs. UUO kidney
of MMP-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-?1-treated MRPECs of MMP-9 WT but not MMP-9
KO mice. Inhibition of MMP-9 or Notch signaling prevented rhTGF-?1- or
rhMMP-9-induced ?-SMA and NICD upregulation in MRPECs. UUO kidney of MMP-9 KO
mice 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 of MRPECs.
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