Overexpression of the serpin megsin induces progressive mesangial cell proliferation and expansion.
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.
Miyata
Toshio
T
Molecular and Cellular Nephrology, Institute of Medical Sciences and Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan. t-miyata@is.icc.u-tokai.ac.jp
Inagi
Reiko
R
Nangaku
Masaomi
M
Imasawa
Toshiyuki
T
Sato
Masahiro
M
Izuhara
Yuko
Y
Suzuki
Daisuke
D
Yoshino
Atsusi
A
Onogi
Hiroshi
H
Kimura
Minoru
M
Sugiyama
Satoshi
S
Kurokawa
Kiyoshi
K
D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D002455:Cell Division; D005341:Fibrinolysin / Q000037:antagonists & inhibitors; D015870:Gene Expression; D005920:Glomerular Mesangium / Q000276:immunology / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009393:Nephritis / Q000209:etiology / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015843:Serpins / Q000235:genetics* / Q000276:immunology / Q000502:physiology*
D000936:Antigen-Antibody Complex; D012333:RNA, Messenger; C114170:SERPINB7 protein, human; C491938:Serpinb7 protein, mouse; D015843:Serpins; D005341:Fibrinolysin