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 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.
Isermann
Berend
B
Department of Medicine I and Clinical Chemistry, University of Heidelberg, INF 410, 69120 Heidelberg, Germany. berend.isermann@med.uni-heidelberg.de
Vinnikov
Ilya A
IA
Madhusudhan
Thati
T
Herzog
Stefanie
S
Kashif
Muhammed
M
Blautzik
Janusch
J
Corat
Marcus A F
MA
Zeier
Martin
M
Blessing
Erwin
E
Oh
Jun
J
Gerlitz
Bruce
B
Berg
David T
DT
Grinnell
Brian W
BW
Chavakis
Triantafyllos
T
Esmon
Charles T
CT
Weiler
Hartmut
H
Bierhaus
Angelika
A
Nawroth
Peter P
PP
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
D011486:Protein C; D018180:Thrombomodulin