Amelioration of Crescentic Glomerulonephritis by RhoA Kinase Inhibitor, Fasudil, through Podocyte Protection and Prevention of Leukocyte Migration.

Amelioration of Crescentic Glomerulonephritis by RhoA Kinase Inhibitor, Fasudil, through Podocyte Protection and Prevention of Leukocyte Migration. Research Abstract Details 

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Amelioration of Crescentic Glomerulonephritis by RhoA Kinase Inhibitor, Fasudil, through Podocyte Protection and Prevention of Leukocyte Migration. Abstract Text:

Teruo Hidaka,Yusuke Suzuki,Michifumi Yamashita,Terumi Shibata,Yuichi Tanaka,Satoshi Horikoshi,Yasuhiko Tomino,

The small GTPase RhoA is activated by the angiotensin II (AngII) type 1 receptor (AT1R), which is part of the local renin-angiotensin system that is involved in podocyte injury preceding glomerular crescent formation. We demonstrated previously that inhibition of AT1R protects against crescentic glomerular injury in Fc receptor-deficient mice (gamma(-/-)) with anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM GN). Here, we hypothesized that the RhoA kinase inhibitor, fasudil, attenuates AT1R-dependent crescentic GN. We examined anti-GBM GN in gamma(-/-) mice with or without fasudil treatment, and further investigated the underlying mechanisms in cultured differentiated podocytes and leukocytes. Fasudil markedly attenuated crescentic GN with a significant decrease in proteinuria and hematuria, infiltration of T cells and monocytes/macrophages as well as their local proliferation, and preservation of podocyte-specific proteins, including WT-1 and nephrin, in glomeruli. In vitro studies showed that AngII induced the down-regulation of both nephrin and WT-1 expression in podocytes, which was reversed by fasudil in a dose-dependent manner. Additionally, fasudil blocked the AngII-induced migration of both macrophages and T cells. Furthermore, we also examined lipopolysaccharide-induced nephrotic syndrome in severe combined immunodeficiency disease mice and found that fasudil failed to block the development of proteinuria because of a B7-1-dependent podocyte injury. In conclusion, fasudil treatment prevents crescent formation and disease progression in anti-GBM GN by preventing AngII-induced podocyte injury and leukocyte migration.

Amelioration of Crescentic Glomerulonephritis by RhoA Kinase Inhibitor, Fasudil, through Podocyte Protection and Prevention of Leukocyte Migration. Publishing Authors By Initials

T Hidaka,Y Suzuki,M Yamashita,T Shibata,Y Tanaka,S Horikoshi,Y Tomino,

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Amelioration of Crescentic Glomerulonephritis by RhoA Kinase Inhibitor, Fasudil, through Podocyte Protection and Prevention of Leukocyte Migration. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: The American journal of pathology

VOLUME: 172

Page Numbers: 603-14

Journal Abbreviation: Am. J. Pathol.

ISSN: 0002-9440

DAY: 2

MONTH: 02

YEAR: 2008

Amelioration of Crescentic Glomerulonephritis by RhoA Kinase Inhibitor, Fasudil, through Podocyte Protection and Prevention of Leukocyte Migration. Information

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LANGUAGE: eng

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AFFILIATION: Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. yasu@med.

Country: United States

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MEDLINETA: Am J Pathol

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