Amelioration of crescentic glomerulonephritis by RhoA kinase inhibitor, Fasudil, through podocyte protection and prevention of leukocyte migration.
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.
Hidaka
Teruo
T
Department of Internal Medicine, Division of Nephrology, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Suzuki
Yusuke
Y
Yamashita
Michifumi
M
Shibata
Terumi
T
Tanaka
Yuichi
Y
Horikoshi
Satoshi
S
Tomino
Yasuhiko
Y
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001806:Blood Urea Nitrogen; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D019610:Cytoprotection / Q000187:drug effects; D005260:Female; D005921:Glomerulonephritis / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D050199:Podocytes / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017452:Receptors, IgG / Q000235:genetics; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors
D047428:Protein Kinase Inhibitors; D017452:Receptors, IgG; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D020742:rhoA GTP-Binding Protein; C049347:fasudil