Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mesangial cells maintain normal glomerular function by mediating ECM remodeling and immune complex disposal. We have recently identified megsin, a novel member of the serine protease inhibitor (serpin) superfamily predominantly expressed in the mesangium. While our previous studies suggested a role for megsin in the pathogenesis of human glomerular diseases, its exact biological significance remained unknown. Here we produced two lines of megsin transgenic mice. Overexpression of megsin led to progressive mesangial matrix expansion and an increase in the number of mesangial cells. These glomerular lesions were accompanied by an augmented immune complex deposition, together with Ig's and complement. Binding and functional assays in vitro identified plasmin as one biological substrate of megsin and confirmed its activity as a proteinase inhibitor. Transgenic animals exhibiting nephritis as a result of treatment with anti--glomerular basement membrane antiserum showed significantly more persistent expansion of the mesangial ECM than was seen in parental mice. Megsin therefore exerts a biologically relevant influence on mesangial function, and on the mesangial microenvironment, such that simple overexpression of this endogenous serpin engenders elementary mesangial lesions.
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PMID:Overexpression of the serpin megsin induces progressive mesangial cell proliferation and expansion. 1187 66

We obtained the "gene profile" of cultured human mesangial cells, and discovered five unknown genes predominantly expressed in mesangial cells. Megsin is one of these novel genes, and sequencing analysis of megsin showed that megsin belongs to the serpin (serine protease inhibitor) superfamily. The characteristics of megsin as a functional serpin are highly conserved among different species, including mice and rats. Expression of megsin is up-regulated in a variety of diseases with mesangial injury in humans and in animal models. We analyzed the promoter region of megsin and identified one positive regulatory motif, an incomplete activator protein-1 (AP-1) binding site within the region. Transgenic mice overexpressing megsin developed mesangial expansion and hypercellularity, which was associated with glomerular immune complex deposition. Our in vitro assays identified plasmin as a candidate target of megsin, although it is likely that megsin has other biological ligands in vivo. These results suggest that megsin plays an essential role in modulating the biological functions of mesangial cells. Megsin may play a role in the regulation of a wide variety of processes in mesangial cells, such as matrix metabolism, cell proliferation, and apoptosis. Identification of the exact biological functions and target proteases of megsin will lead us to develop novel therapeutic approaches to glomerular diseases.
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PMID:Mesangial cell-predominant functional gene, megsin. 1458 25

In diabetic nephropathy decreased activities of matrix metalloproteinase (MMP)-2, MMP-9 and plasmin contribute to mesangial matrix accumulation. Megsin, a novel member of the serine protease inhibitor superfamily, is predominantly expressed in mesangial cells and is up-regulated in diabetic nephropathy and its overexpression spontaneously induces progressive mesangial expansion in mice. High-glucose stimulated megsin mRNA expression in an in vivo model of type II diabetic nephropathy as well as in vitro in cultured mesangial cells. Megsin potentially inhibits total enzymatic activities of MMP-2 and -9 and plasmin, indicating decreased degradation of mesangial matrix. A specific monoclonal anti-megsin neutralizing antibody restored MMP activity in a transforming growth factor-beta independent manner. Our study suggests that the mesangial matrix accumulation caused by hyperglycemia in diabetes might be due at least in part to up-regulation of megsin which can inhibit plasmin and MMP activities.
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PMID:The role of megsin, a serine protease inhibitor, in diabetic mesangial matrix accumulation. 1858 Aug 57