title: Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis.
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.
authors.affiliation: Department of Medicine I and Clinical Chemistry, University of Heidelberg, INF 410, 69120 Heidelberg, Germany. berend.isermann@med.uni-heidelberg.de
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
authors.forename: Ilya A
authors.initials: IA
authors.lastname: Vinnikov
authors.forename: Thati
authors.initials: T
authors.lastname: Madhusudhan
authors.forename: Stefanie
authors.initials: S
authors.lastname: Herzog
authors.forename: Muhammed
authors.initials: M
authors.lastname: Kashif
authors.forename: Janusch
authors.initials: J
authors.lastname: Blautzik
authors.forename: Marcus A F
authors.initials: MA
authors.lastname: Corat
authors.forename: Martin
authors.initials: M
authors.lastname: Zeier
authors.forename: Erwin
authors.initials: E
authors.lastname: Blessing
authors.forename: Jun
authors.initials: J
authors.lastname: Oh
authors.forename: Bruce
authors.initials: B
authors.lastname: Gerlitz
authors.forename: David T
authors.initials: DT
authors.lastname: Berg
authors.forename: Brian W
authors.initials: BW
authors.lastname: Grinnell
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.forename: Charles T
authors.initials: CT
authors.lastname: Esmon
authors.forename: Hartmut
authors.initials: H
authors.lastname: Weiler
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D019610:Cytoprotection / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D004730:Endothelium, Vascular / Q000201:enzymology / Q000473:pathology*; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D007678:Kidney Glomerulus / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008833:Microcirculation / Q000201:enzymology / Q000473:pathology; D050199:Podocytes / Q000201:enzymology / Q000473:pathology*; D011486:Protein C / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D018180:Thrombomodulin / Q000502:physiology
chemical_list: D011486:Protein C; D018180:Thrombomodulin