Overexpression of the serpin megsin induces progressive mesangial cell proliferation and expansion

被引:58
|
作者
Miyata, T [1 ]
Inagi, R
Nangaku, M
Imasawa, T
Sato, M
Izuhara, Y
Suzuki, D
Yoshino, A
Onogi, H
Kimura, M
Sugiyama, S
Kurokawa, K
机构
[1] Tokai Univ, Sch Med, Inst Med Sci, Isehara, Kanagawa 2591193, Japan
[2] Tokai Univ, Sch Med, Dept Internal Med, Isehara, Kanagawa 2591193, Japan
[3] Univ Tokyo, Sch Med, Div Nephrol & Endocrinol, Tokyo 113, Japan
[4] Fujita Hlth Univ, Sch Med, Div Nephrol, Aichi, Japan
来源
JOURNAL OF CLINICAL INVESTIGATION | 2002年 / 109卷 / 05期
关键词
D O I
10.1172/JCI200214336
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:585 / 593
页数:9
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