Increased expression of plasminogen activator inhibitor-1 with fibrin deposition in a murine model of aging, "Klotho" mouse.
Although aging accompanies specific pathological changes, including thrombosis and organ sclerosis, the underlying mechanisms of these processes remain to be elucidated. In the present study, we analyzed the gene expression of plasminogen activator inhibitor-1 (PAI-1), a key molecule in the development of thrombosis, in a murine model of aging, klotho mutant ( kl/kl) mice. Active PAI-1 antigen in plasma and PAI-1 mRNA in several tissues were strikingly elevated in kl/kl mice as compared with wild-type mice. This increased PAI-1 expression was age dependent and linked to the development of ectopic calcification and glomerular fibrin deposition in the kidneys. In situ hybridization analysis of kl/kl mice demonstrated that strong signals for PAI-1 mRNA were localized in renal tubular epithelial cells, cardiomyocytes, adrenal medullar cells, and smooth muscle and endothelial cells in Mönckeberg's arteriosclerotic vessels. Renal glomerular fibrin deposition, as evaluated immunohistochemically, was occasionally observed only in kl/kl mice, and the number of fibrin-positive glomeruli increased as the kl/kl mice aged. These observations suggest that in the process of aging the PAI-1 gene expression is increased, contributing to the development of thrombosis.
Takeshita
Kyosuke
K
First Department of Internal Medicine, Nagoya University School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan.
Yamamoto
Koji
K
Ito
Masafumi
M
Kondo
Takahisa
T
Matsushita
Tadashi
T
Hirai
Makoto
M
Kojima
Tetsuhito
T
Nishimura
Masahiko
M
Nabeshima
Yoichi
Y
Loskutoff
David J
DJ
Saito
Hidehiko
H
Murohara
Toyoaki
T
D000375:Aging / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D005337:Fibrin / Q000378:metabolism*; D015870:Gene Expression; D005966:Glucuronidase; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D000090265:Klotho Proteins; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D023421:Models, Animal; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013927:Thrombosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution
D008565:Membrane Proteins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D005337:Fibrin; D005966:Glucuronidase; D000090265:Klotho Proteins