The role of megsin, a serine protease inhibitor, in diabetic mesangial matrix accumulation.
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.
Ohtomo
Shuichi
S
Institute of Medical Sciences, Tokai University, Kanagawa, Japan.
Nangaku
Masaomi
M
Izuhara
Yuko
Y
Yamada
Norio
N
Dan
Takashi
T
Mori
Takefumi
T
Ito
Sadayoshi
S
van Ypersele de Strihou
Charles
C
Miyata
Toshio
T
D000818:Animals; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D005109:Extracellular Matrix / Q000201:enzymology / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D050527:Mesangial Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000502:physiology*; D015843:Serpins / Q000235:genetics / Q000502:physiology*; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics
C114170:SERPINB7 protein, human; D015842:Serine Proteinase Inhibitors; D015843:Serpins; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D019716:Tissue Inhibitor of Metalloproteinase-2; D005341:Fibrinolysin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9