Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nat Med 2007 Nov;13(11):1349-58
Date
11/06/2007Pubmed ID
17982464DOI
10.1038/nm1667Scopus ID
2-s2.0-35948934636 (requires institutional sign-in at Scopus site) 345 CitationsAbstract
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.
Author List
Isermann B, Vinnikov IA, Madhusudhan T, Herzog S, Kashif M, Blautzik J, Corat MA, Zeier M, Blessing E, Oh J, Gerlitz B, Berg DT, Grinnell BW, Chavakis T, Esmon CT, Weiler H, Bierhaus A, Nawroth PPAuthor
Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Amino Acid SubstitutionAnimals
Apoptosis
Cell Line, Transformed
Cells, Cultured
Cytoprotection
Diabetes Mellitus, Experimental
Diabetic Nephropathies
Endothelium, Vascular
Enzyme Activation
Humans
Kidney Glomerulus
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Mice, Transgenic
Microcirculation
Podocytes
Protein C
Signal Transduction
Thrombomodulin