Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

Tan, Thian Kui, Zheng, Guoping, Hsu, Tzu-Ting, Lee, So Ra, Zhang, Jianlin, Zhao, Ye, Tian, Xinrui, Wang, Yiping, Wang, Yuan Min, Cao, Qi, Wang, Ya, Lee, Vincent W.S., Wang, Changqi, Zheng, Dong, Alexander, Stephen I., Thompson, Erik, & Harris, David C. H. (2013) Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage. Laboratory Investigation, 93(4), pp. 434-449.

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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.

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32 citations in Scopus
28 citations in Web of Science®
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ID Code: 71133
Item Type: Journal Article
Refereed: Yes
Additional Information: Cited By (since 1996):1
Export Date: 6 May 2014
Source: Scopus
PubMed ID: 23358111
Keywords: Epithelial-mesenchymal transition, macrophage, matrix metalloproteinase-9, osteopontin, renal fibrosis, tubular epithelial cell
DOI: 10.1038/labinvest.2013.3
ISSN: 0023-6837
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Deposited On: 07 May 2014 03:07
Last Modified: 21 Jun 2017 05:02

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