Mice lacking the matrix metalloproteinase-9 gene reduce renal interstitial fibrosis in obstructive nephropathy

Wang, Xiaohua; Zhou, Yang; Tan, Ruoyun; Xiong, Min; He, Weichun; Li, Fang; Wen, Ping; Jiang, Lei; Yang, Junwei

doi:10.1152/ajprenal.00216.2010

Cited by 103 publications

(96 citation statements)

References 37 publications

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“…In the current study, we showed that inhibition of MMP-9 activity by an MMP-2/9 inhibitor or MMP-9 Ab, specifically at early or late stages of UUO, was protective against the development of renal fibrosis. This result is consistent with a role of MMP-9 in renal fibrosis, which was previously reported, 19,39 however the mechanism underlying its contribution was not fully explained. To the best of our knowledge, our study is the first to demonstrate a stage-specific expression of MMP-9 in renal fibrosis and its relevance to stage-specific therapy.…”

Section: Discussionsupporting

confidence: 89%

“…Previous studies by Yang et al 19,39 demonstrated that direct or indirect inhibition of MMP-9 activity resulted in a reduction in tubular cell EMT and renal fibrosis in obstructive nephropathy. Findings from our current study further extended those observations where early-and latestage inhibition of MMP-9 not only reduced tubular cell EMT and renal fibrosis but also reduced MMP-9-cleaved OPN and macrophage infiltration.…”

Section: Discussionmentioning

confidence: 96%

“…17 MMP-9 is well established to have a role in tubular cell EMT, 9,18 in fact induction of tubular cell EMT in vitro and in vivo is associated with increased expression of MMP-9. Although MMP-9 knockout (KO) has been shown to reduce tubular cell EMT and renal fibrosis in murine unilateral ureteral obstruction (UUO) model, 19 interpretation of results obtained from the KO mice may have oversimplified the biological complexity of MMP-9. Moreover, the use of MMP-KO model has yielded conflicting results in various disease models.…”

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confidence: 99%

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

Tan

Zheng

Hsu

et al. 2013

Laboratory Investigation

129

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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. KEYWORDS: Epithelial-mesenchymal transition; macrophage; matrix metalloproteinase-9; osteopontin; renal fibrosis; tubular epithelial cell Matrix metalloproteinase-9 (MMP-9), also known as gelatinase B, belongs to a large family of zinc-dependent matrixdegrading enzymes called matrix metalloproteinases (MMPs) that have an important role in both physiological and pathological conditions in vivo. 1 MMPs are well known for their anti-fibrotic effect due to their ability to degrade and remodel extracellular matrix (ECM) proteins, however it has been recognized that MMPs can also exert pro-fibrotic effect under various pathological conditions.Myofibroblasts are the effector cells responsible for the production and secretion of ECM in renal fibrosis. It has been reported that myofibroblasts can derive from the activation of renal interstitial fibroblasts, perivascular fibroblasts and pericytes, from bone marrow-derived stem cells and

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

See 1 more Smart Citation

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

Tan

Zheng

Hsu

et al. 2013

Laboratory Investigation

129

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“…With regard to MMP-9, a recent study demonstrated that mice lacking the MMP-9 gene show mild renal interstitial fibrosis in unilateral ureteral obstruction (UUO). 22 However, the therapeutic effect of MMP-2 inhibition on progressive renal fibrosis is still uncertain.…”

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confidence: 99%

Involvement of matrix metalloproteinase-2 in the development of renal interstitial fibrosis in mouse obstructive nephropathy

Shimizu

Masuda

et al. 2012

Laboratory Investigation

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“…1 Metabolize dysfunction of MMP-9 was reported to take part in the pathogenesis of renal diseases. [2][3][4] The homeostasis of ECM is destroyed, which is an important characteristic of renal diseases. MMP-9 is one of the most important MMPs for the ECM degradation.…”

Section: Introductionmentioning

confidence: 99%

Association of Matrix Metalloproteinase-9 Level with the Risk of Renal Involvement for Henoch–Schönlein Purpura in Children

Zhou

Yin

2013

Renal Failure

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Matrix metalloproteinase-9 (MMP-9) is an enzyme that implicates in the pathogenesis of renal diseases. HenochSchönlein purpura nephritis (HSPN) is the most serious long-term complication of Henoch-Schönlein purpura, and it is one of the most common renal diseases in children. There was no any meta-analysis to explore the association of MMP-9 level with the risk of HSPN, and this meta-analysis was performed to evaluate the association between MMP-9 level and HSPN risk in children. A predefined literature search and selection of eligible relevant studies were performed to collect data from electronic databases. Eight articles were identified for the analysis of association between MMP-9 level and HSPN risk in children. In this meta-analysis, urinary MMP-9 level was associated with the risk of HSPN [odds ratio (OR) ¼ 77.21, 95% confidence interval (CI): 54.56-99.86, p < 0.00001]. Furthermore, there was a notably difference for the association of the serum MMP-9 level with HSPN risk (OR ¼ 135.91, 95% CI: 82.54-189.27, p < 0.00001). In conclusion, urinary/serum MMP-9 level is associated with the risk of HSPN. However, the data used for the meta-analysis in this article were from some low-level studies with small samples, and more studies should be performed in the future.Keywords: matrix metalloproteinase-9 (MMP-9), Henoch-Schönlein purpura nephritis (HSPN), urinary MMP-9, serum MMP-9, meta-analysis

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Mice lacking the matrix metalloproteinase-9 gene reduce renal interstitial fibrosis in obstructive nephropathy

Abstract: . Mice lacking the matrix metalloproteinase-9 gene reduce renal interstitial fibrosis in obstructive nephropathy.

Cited by 103 publications

References 37 publications

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

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

Involvement of matrix metalloproteinase-2 in the development of renal interstitial fibrosis in mouse obstructive nephropathy

Association of Matrix Metalloproteinase-9 Level with the Risk of Renal Involvement for Henoch–Schönlein Purpura in Children

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