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      TNF-Alpha and IL-1Beta-Mediated Regulation of MMP-9 and TIMP-1 in Human Glomerular Mesangial Cells

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          Background: Renal cells such as mesangial cells are known to secrete metalloproteinases that are capable of degrading the constituents of the glomerular basement membrane (GBM). Disruption of the GBM via cytokine-induced alterations in matrixmetalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) may be an important mechanism in the renal disease process. In renal disease, both resident renal cells and infiltrating immune cells are capable of secreting pro-inflammatory cytokines including tumour necrosing factor-α (TNFα) and interleukin-1β (IL-1β). In this study, we examine the potential of these cytokines to alter levels of MMPs and TIMPs in human mesangial cells. Methods: The T-HMC human mesangial cell line was cultured in RPMI 1640 containing 5% serum. Cells at confluency were serum starved for 24 h prior to exposure to TNF-α (0.1–100 ng/ml) or IL-1β (0.1–100 ng/ml) or a combination of both for 48 h. Activity of MMP-9 was examined by gelatin zymography and TIMP-1 expression was analysed by Western blotting. Results: TNF-α but not IL-1β resulted in a dose-dependent increase in the latent form of MMP-9 and a decrease in TIMP-1 production. Co-treatment with IL-1β had no effect on the induction of MMP-9 but increased the inhibition of TIMP-1 in the presence of TNF-α. Inhibition of PKC provided evidence of the importance of this pathway in mediating the TNF-α-induced suppression of TIMP-1. Activation of the ERK 1/2 MAPK mediated both the upregulation of MMP-9 and the inhibition of TIMP-1 following TNF-α treatment. p38 MAPK activation was also found to be involved in the TNF-α-stimulated MMP-9. Conclusion: The cytokine TNF-α causes different effects on human mesangial MMP-9 and TIMP-1 expression which are mediated through the TNF-RI, and the different signalling pathways of PKC, ERK 1/2 and p38 MAPK. This suggests an important role for pro-inflammatory cytokines in renal disease progression.

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          Most cited references 32

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          Secretory products of macrophages.

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            Role of matrix metalloproteinases in renal pathophysiologies.

            Matrix metalloproteinases (MMPs) are a large family of proteinases that remodel extracellular matrix (ECM) components and cleave a number of cell surface proteins. MMP activity is regulated via a number of mechanisms, including inhibition by tissue inhibitors of metalloproteinases (TIMPs). Originally thought to cleave only ECM proteins, MMP substrates are now known to include signaling molecules (growth factor receptors) and cell adhesion molecules. Recent data suggest a role for MMPs in a number of renal pathophysiologies, both acute and chronic. This review will focus on the expression and localization of MMPs and TIMPs in the kidney, as well as summarizing the current information linking these proteins to acute kidney injury, glomerulosclerosis/tubulointerstitial fibrosis, chronic allograft nephropathy, diabetic nephropathy, polycystic kidney disease, and renal cell carcinoma.
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              The progression of renal disease.

              The diversity of its causes, the unpredictability of its clinical course, and our expanding knowledge of the conditions that may exacerbate or retard its progression suggest that glomerular sclerosis cannot be attributed to a single aberration in glomerular physiology. Nonetheless, the welter of clinical and experimental observations is beginning to yield a pattern. Agents or conditions injurious to glomerular epithelium tend to cause glomerular sclerosis. Agents or conditions that induce short-term or long-term activation of mesangial cells may lead to glomerular sclerosis. Indeed, one contribution of the healthy epithelium may be to serve as a tonic inhibitor of the intraglomerular processes arising from mesangial-cell activation. Long-term activation of the mesangium is associated with the proliferation and infiltration of cells and with the expansion of the mesangial matrix--the antecedents of sclerosis. We anticipate that different diseases associated with glomerular sclerosis will be found to depend to varying extents on these two potential mechanisms of sclerosis. Beyond a certain threshold of glomerular injury, glomerular diseases share an additional factor: the capacity of both intrinsic cells and infiltrating cells to alter the microenvironment of the glomerulus so that sclerosis progresses inexorably long after the disappearance of the initiating insult. Several potential risk factors may contribute to the progression of chronic renal disease. These factors include systemic hypertension, proteinuria, hyperlipidemia, high protein intake, and probably conditions that lead to glomerular hypertrophy. Interventions designed to minimize the potential contribution of these factors to the progression of renal insufficiency may halt or slow the loss of function of the kidney. Clinical trials designed to examine the effects of these factors on the progressive course of renal insufficiency will help to establish their role and relative importance in humans.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                October 2007
                20 September 2007
                : 107
                : 2
                : e73-e86
                School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland
                108645 Nephron Exp Nephrol 2007;107:e73–e86
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 9, References: 44, Pages: 1
                Original Paper


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