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Article
Nature Medicine 13, 1349 - 1358 (2007)
Published online: 4 November 2007 | doi:10.1038/nm1667
Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis
Berend Isermann1,10, Ilya A Vinnikov1,10, Thati Madhusudhan1,10, Stefanie Herzog1, Muhammed Kashif1, Janusch Blautzik1, Marcus A F Corat2,9, Martin Zeier3, Erwin Blessing4, Jun Oh5, Bruce Gerlitz6, David T Berg6, Brian W Grinnell6, Triantafyllos Chavakis7, Charles T Esmon8, Hartmut Weiler2, Angelika Bierhaus1 & Peter P Nawroth1
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.
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