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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Veröffentlicht in:Nature medicine Jg. 13; H. 11; S. 1349 - 1358
Hauptverfasser: 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
Format: Journal Article
Sprache:Englisch
Veröffentlicht: New York Nature Publishing Group US 01.11.2007
Nature Publishing Group
Schlagworte:
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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Zusammenfassung: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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ISSN:1078-8956
1546-170X
DOI:10.1038/nm1667