Inhibition of Matrix Metalloproteinases During Chronic Allograft Nephropathy in Rats

Lutz, Jens; Yao, Yousheng; Song, Erwei; Antus, Balázs; Hamar, Péter; Liu, Shanying; Heemann, Uwe

doi:10.1097/01.tp.0000151644.85832.b5

Cited by 61 publications

(53 citation statements)

References 44 publications

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“…These results suggest that early events could have started from implantation or during early AR may lead to early rises in MMP activity, such as those associated with inflammatory cell invasion and penetration of basement membranes, thus damaging or altering composition of the ECM, while later loses in ECM turnover may lead to ECM accumulation. 18 Their data in an animal model does, however, conflict with what we report in this human study.…”

Section: Discussioncontrasting

confidence: 56%

“…16 It is surprising that there is a paucity of data on the role of these enzymes and their contribution to the pathogenesis of CAN in comparison to the bulk of studies delineating their role in chronic kidney disease. 18 Limited studies have measured serum proMMP-1, proMMP-2, and proMMP-3 in acute renal allograft rejection, and CAN as a reflection of stimulation induced by several inflammatory cytokines in progression of CAN. 19,20 None of the studies have located MMP/TIMP members in CAN, or, more importantly, assessed the net proteolytic activity in different compartments (glomerular vs tubulo-interstitial) of the transplanted kidney.…”

Section: Introductionmentioning

confidence: 99%

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Changes in Matrix Metalloproteinases and Their Inhibitors in Kidney Transplant Recipients

Ak¹,

Nahas²,

Ts³

2012

Exp Clin Transplant

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Objectives: Chronic allograft nephropathy remains one of the main causes of late graft loss after kidney transplant owing to multifactorial development of kidney scarring. Chronic allograft nephropathy is characterised by an excess accumulation of extracellular matrix. A key system regulating extracellular matrix homeostasis are matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases. This study sought to determine if a change in the matrix metalloproteinases/tissue inhibitors of matrix metalloproteinases system contributes to chronic allograft nephropathy-associated progressive kidney scarring. Materials and Methods: Examination of sequential renal biopsies was done at implantation, acute rejection, and subsequent chronic allograft nephropathy. In situ localisation of matrix metalloproteinase activity was assessed with a high-resolution in situ zymography technique using gelatin and collagen 1 substrates. Matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases were localised using immunohistochemistry. Results: In situ zymography showed over a 50% reduction in matrix metalloproteinase activity against both collagen 1 and gelatin substrates in chronic allograft nephropathy biopsies. A similar loss of matrix metalloproteinase activity was seen in the glomerular and tubulointerstitial compartments.Immunoreactive matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases were observed intracellularly in mesangial and tubular epithelial cells. Matrix metalloproteinases-1, -2, -3, and -9 were significantly reduced in acute rejection and later in chronic allograft nephropathy. However, glomerular matrix metalloproteinases 1 and 9 and tubulointerstitial matrix metalloproteinase-2 were reduced at implantation. Tissue inhibitors of matrix metalloproteinase-2 and -3 were elevated from implantation onwards. We were unable to stain reproducibly for tissue inhibitors of matrix metalloproteinase-1. Conclusions: Kidney scarring underlying chronic allograft nephropathy is associated with a reduction in matrix metalloproteinases activity that may be due to reduced expression of matrix metalloproteinases -1, -2, -3, and -9, and upregulation of tissue inhibitors of matrix metalloproteinases -2 and -3. Some of these changes originate from implantation.

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Section: Discussioncontrasting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Changes in Matrix Metalloproteinases and Their Inhibitors in Kidney Transplant Recipients

Ak¹,

Nahas²,

Ts³

2012

Exp Clin Transplant

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“…Furthermore, MMPs including MMP-9 has been shown to exhibit an opposing role at different stages of disease progression including renal disease. [26][27][28] Overall, the above observations highlight the complex biological function of MMP-9 that has previously 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 in UUO model via MMP-9 inhibition.…”

mentioning

confidence: 86%

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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“…Erken dönemde MMP baskılanması matriks yıkımı ve bunun sonucunda tetiklenen yeniden yapım ve fibrozisi engellerken, geç dönemdeki baskılanma, oluşmuş olan fibrotik dokunun uzaklaşmasını engelleyerek fibrozis oluşumunu daha da artırmaktadır. Bu sonuç MMP'lerin KAN gelişiminde ve ilerlemesinde rol aldığını desteklemektedir (17). Birçok kanser türünde de MMP'lerin işlevleri araştırılmıştır.…”

Section: Türk Nefroloji Diyaliz Ve Transplantasyon Dergisi Turkish Neunclassified

The Role of Matrix Metalloproteinases in Renal Diseases

Sağlam¹

2010

Turk Neph Dial Transpl

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özMatriks metaloproteinazlar (MMP) çinko bağımlı, geniş bir aileye mensup enzimler olup, hücre dışı matriks yıkımının ana düzenleyicileridirler ve böbrek hastalıklarındaki rolleri giderek daha iyi anlaşılmaktadır. Birçok ilerleyici böbrek hastalığı, süregen hücre çoğalması ve mezengiyal hücreler tarafından hücre dışı matriksin anormal yapımı ile karakterizedir. Bu nedenle mezengiyal hücre çoğalması ve hücre dışı matriks metabolizmasını düzenleyen faktörlerin bilinmesi önem kazanmaktadır. Böbrek glomerüler hücrelerinde MMP'lerin üretilip salındığı, interstisiyel fibroblast ve tubüloepitelyal hücrelerin de MMP salgıladığı gösterilmiştir. MMP'ler böbrekteki yayılımcı hücre davranışı, embriyonik gelişim ve doku fibrozisi olaylarında görev alırlar. Yangı ve yeniden yapılanma işlemlerinde de MMP'lerin yapımlarının arttığı bilinmektedir. Gerek deneysel, gerekse klinik çalışmalardan elde edilen veriler sonucunda; proliferatif glomerülonefritler, hipertansif nefropati, diyabetik nefropati, HİV nefropatisi, toksik nefropati, obstrüktif nefropati, renal hücreli karsinom, kronik allograft nefropati ilişkili fibrozis ve daha birçok böbrek hastalığında MMP'lerin rolleri gösterilmiştir. Bu veriler eşliğinde, MMP'leri hedef alan tedavi seçenekleri gündeme gelmiştir. Yakın zamanlı çalışmalarda elde edilen sınırlı sayıdaki bulgular; MMP baskılayıcı tedavilerin gelecekte klinik uygulamalarda yer almaları konusunda umut verici görünmektedir. Bu derlemede yangı ve yeniden yapılanma işlemlerinde yapımları artan MMP'lerin, böbrek hastalıklarındaki rolleri ve gelecekteki tedavi seçenekleri tartışılacaktır.anaHTaR SözCÜKlER: Böbrek hastalıkları, Hücre dışı matriks aBSTRaCT Matrix metalloproteinases (MMPs) are a family of zinc dependent proteinases and the main promoters of extracellular matrix degradation. Their role in renal diseases is now being understood better. Several progressive renal diseases are characterized with persistent cell proliferation and abnormal production of extracellular matrix by mesengial cells. Understanding mesengial cell proliferation and the factors regulating extracellular matrix metabolism is therefore becoming more important. MMPs have been shown to be produced and excreted from renal glomerular cells and interstitital fibroblast and tubuloepithelial cells have also been shown to excrete MMPs. MMPs function in expansive cell behaviour, embryonic evolution and tissue fibrosis. Production of MMPs are known to increase in inflammation and restructure processes. Data obtained from both experimental and clinical studies has shown the role of MMPs in proliferative glomerulonephritis, hypertensive nephropathy, diabetic nephropathy, HIV nephropathy, toxic nephropathy, obstructive nephropathy, renal cell carcinoma, chronic allograft nephropathy-related fibrosis and in many other renal diseases. In light of these data, therapy options targeting MMPs have become a current issue. Limited data obtained from recent studies are promising about the clinical use of therapies repressing MMPs in future. The roles of MMPs whi...

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Inhibition of Matrix Metalloproteinases During Chronic Allograft Nephropathy in Rats

Abstract: Inhibition of MMPs early after transplantation reduced the development and progression of CAN but promoted CAN if initiated at later stages. Thus, MMPs are involved in the development and progression of CAN.

Cited by 61 publications

References 44 publications

Changes in Matrix Metalloproteinases and Their Inhibitors in Kidney Transplant Recipients

Changes in Matrix Metalloproteinases and Their Inhibitors in Kidney Transplant Recipients

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

The Role of Matrix Metalloproteinases in Renal Diseases

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