Overexpression of the serpin megsin induces progressive mesangial cell proliferation and expansion
Overexpression of the serpin megsin induces progressive mesangial cell proliferation and expansion
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DOI：
10.1172/jci200214336
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发表时间：
2002-03-01
影响因子：
15.9
通讯作者：
Kurokawa, K
中科院分区：
文献类型：
--
作者：
Miyata, T;Inagi, R;Kurokawa, K
肾小球系膜细胞通过介导细胞外基质重塑和免疫复合物的处理来维持肾小球的正常功能。我们最近确定了megsin，丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂）超家族的一个新成员，主要在系膜中表达。虽然我们以前的研究表明megsin在人类肾小球疾病的发病机制中发挥作用，但其确切的生物学意义仍然未知。在这里，我们生产了两种megsin转基因小鼠。megsin的过度表达导致肾小球系膜基质扩张和系膜细胞数量的增加。这些肾小球病变伴有免疫复合物沉积增加，以及IG和补体。体外结合试验和功能试验证实纤溶酶是巨噬细胞毒素的生物底物之一，并证实其具有蛋白酶抑制剂的活性。抗肾小球基底膜抗血清治疗的转基因动物表现出肾炎，表现出比亲代小鼠更持久的系膜ECM扩张。因此，Megsin对系膜功能和系膜微环境产生生物学相关影响，使得这种内源性丝氨酸蛋白酶抑制剂的简单过表达产生初级系膜病变。
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. Bindin g 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.