Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis

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 linke...

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Vydáno v:	Nature medicine Ročník 13; číslo 11; s. 1349 - 1358
Hlavní autoři:	Isermann, Berend, Vinnikov, Ilya A, Madhusudhan, Thati, Herzog, Stefanie, Kashif, Muhammed, Blautzik, Janusch, Corat, Marcus A F, Zeier, Martin, Blessing, Erwin, Oh, Jun, Gerlitz, Bruce, Berg, David T, Grinnell, Brian W, Chavakis, Triantafyllos, Esmon, Charles T, Weiler, Hartmut, Bierhaus, Angelika, Nawroth, Peter P
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	New York Nature Publishing Group US 01.11.2007 Nature Publishing Group
Témata:	Amino Acid Substitution - genetics Animals Apoptosis Apoptosis - genetics Biomedical and Life Sciences Biomedicine Cancer Research Cell Line, Transformed Cells, Cultured Cellular biology Cytoprotection - genetics Diabetes Diabetes Mellitus, Experimental - enzymology Diabetes Mellitus, Experimental - genetics Diabetes Mellitus, Experimental - pathology Diabetes Mellitus, Experimental - prevention & control Diabetic Nephropathies - enzymology Diabetic Nephropathies - genetics Diabetic Nephropathies - pathology Diabetic Nephropathies - prevention & control Endothelium, Vascular - enzymology Endothelium, Vascular - pathology Enzyme Activation - genetics Filtration Humans Infectious Diseases Kidney diseases Kidney Glomerulus - blood supply Kidney Glomerulus - enzymology Kidney Glomerulus - pathology Metabolic Diseases Mice Mice, Inbred C57BL Mice, Mutant Strains Mice, Transgenic Microcirculation - enzymology Microcirculation - pathology Molecular Medicine Neurosciences Podocytes - enzymology Podocytes - pathology Protein C - biosynthesis Protein C - genetics Protein C - physiology Proteins Rodents Signal Transduction - genetics Thrombomodulin - physiology
ISSN:	1078-8956, 1546-170X
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1078-8956 1546-170X
DOI:	10.1038/nm1667