Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage.
A pro-fibrotic role of matrix metalloproteinase-9 (MMP-9) in tubular cell epithelial-mesenchymal transition (EMT) is well established in renal fibrosis; however studies from our group and others have demonstrated some previously unrecognized complexity of MMP-9 that has been overlooked in renal fibrosis. Therefore, the aim of this study was to determine the expression pattern, origin and the exact mechanism underlying the contribution of MMP-9 to unilateral ureteral obstruction (UUO), a well-established model of renal fibrosis via MMP-9 inhibition. Renal MMP-9 expression in BALB/c mice with UUO was examined on day 1, 3, 5, 7, 9, 11 and 14. To inhibit MMP-9 activity, MMP-2/9 inhibitor or MMP-9-neutralizing antibody was administered daily for 4 consecutive days from day 0-3, 6-9 or 10-13 and tissues harvested at day 14. In UUO, there was a bi-phasic early- and late-stage upregulation of MMP-9 activity. Interestingly, tubular epithelial cells (TECs) were the predominant source of MMP-9 during early stage, whereas TECs, macrophages and myofibroblasts produced MMP-9 during late-stage UUO. Early- and late-stage inhibition of MMP-9 in UUO mice significantly reduced tubular cell EMT and renal fibrosis. Moreover, MMP-9 inhibition caused a significant reduction in MMP-9-cleaved osteopontin and macrophage infiltration in UUO kidney. Our in vitro study showed MMP-9-cleaved osteopontin enhanced macrophage transwell migration and MMP-9 of both primary TEC and macrophage induced tubular cell EMT. In summary, our result suggests that MMP-9 of both TEC and macrophage origin may directly or indirectly contribute to the pathogenesis of renal fibrosis via osteopontin cleavage, which, in turn further recruit macrophage and induce tubular cell EMT. Our study also highlights the time dependency of its expression and the potential of stage-specific inhibition strategy against renal fibrosis.
Centre for Transplant and Renal Research, University of Sydney at Westmead Millennium Institute, Sydney, NSW, Australia.
Thian Kui
TK
Tan
Guoping
G
Zheng
Tzu-Ting
TT
Hsu
So Ra
SR
Lee
Jianlin
J
Zhang
Ye
Y
Zhao
Xinrui
X
Tian
Yiping
Y
Wang
Yuan Min
YM
Wang
Qi
Q
Cao
Ya
Y
Wang
Vincent W S
VW
Lee
Changqi
C
Wang
Dong
D
Zheng
Stephen I
SI
Alexander
Erik
E
Thompson
David C H
DC
Harris
D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D053495:Osteopontin / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014517:Ureteral Obstruction / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D000071250:Snail Family Transcription Factors; C506896:Spp1 protein, mouse; D014157:Transcription Factors; D051176:beta Catenin; D053495:Osteopontin; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse