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Type: Artigo de periódico
Title: Activated Protein C Protects Against Diabetic Nephropathy By Inhibiting Endothelial And Podocyte Apoptosis
Author: Isermann B.
Vinnikov I.A.
Madhusudhan T.
Herzog S.
Kashif M.
Blautzik J.
Corat M.A.F.
Zeier M.
Blessing E.
Oh J.
Gerlitz B.
Berg D.T.
Grinnell B.W.
Chavakis T.
Esmon C.T.
Weiler H.
Bierhaus A.
Nawroth P.P.
Abstract: Data providing direct evidence for a causative link between endothelial dysfunction, microvascular disease and diabetic end-organ damage are scarce. Here we show that activated protein C (APC) formation, which is regulated by endothelial thrombomodulin, is reduced in diabetic mice and causally linked to nephropathy. Thrombomodulin-dependent APC formation mediates cytoprotection in diabetic nephropathy by inhibiting glomerular apoptosis. APC prevents glucose-induced apoptosis in endothelial cells and podocytes, the cellular components of the glomerular filtration barrier. APC modulates the mitochondrial apoptosis pathway via the protease-activated receptor PAR-1 and the endothelial protein C receptor EPCR in glucose-stressed cells. These experiments establish a new pathway, in which hyperglycemia impairs endothelial thrombomodulin- dependent APC formation. Loss of thrombomodulin-dependent APC formation interrupts cross-talk between the vascular compartment and podocytes, causing glomerular apoptosis and diabetic nephropathy. Conversely, maintaining high APC levels during long-term diabetes protects against diabetic nephropathy. © 2007 Nature Publishing Group.
Rights: fechado
Identifier DOI: 10.1038/nm1667
Date Issue: 2007
Appears in Collections:Unicamp - Artigos e Outros Documentos

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