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

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

In: NAT MED, Vol. 13, No. 11, 11.2007, p. 1349-58.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Isermann, B, Vinnikov, IA, Madhusudhan, T, Herzog, S, Kashif, M, Blautzik, J, Corat, MAF, Zeier, M, Blessing, E, Oh, J, Gerlitz, B, Berg, DT, Grinnell, BW, Chavakis, T, Esmon, CT, Weiler, H, Bierhaus, A & Nawroth, PP 2007, 'Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis', NAT MED, vol. 13, no. 11, pp. 1349-58. https://doi.org/10.1038/nm1667

APA

Isermann, B., Vinnikov, I. A., Madhusudhan, T., Herzog, S., Kashif, M., Blautzik, J., Corat, M. A. F., Zeier, M., Blessing, E., Oh, J., Gerlitz, B., Berg, D. T., Grinnell, B. W., Chavakis, T., Esmon, C. T., Weiler, H., Bierhaus, A., & Nawroth, P. P. (2007). Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. NAT MED, 13(11), 1349-58. https://doi.org/10.1038/nm1667

Vancouver

Isermann B, Vinnikov IA, Madhusudhan T, Herzog S, Kashif M, Blautzik J et al. Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. NAT MED. 2007 Nov;13(11):1349-58. https://doi.org/10.1038/nm1667

Bibtex

@article{a1e76b316bc14237b4e2563e3d21de45,
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.",
keywords = "Amino Acid Substitution/genetics, Animals, Apoptosis/genetics, Cell Line, Transformed, Cells, Cultured, Cytoprotection/genetics, Diabetes Mellitus, Experimental/enzymology, Diabetic Nephropathies/enzymology, Endothelium, Vascular/enzymology, Enzyme Activation/genetics, Humans, Kidney Glomerulus/blood supply, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Mice, Transgenic, Microcirculation/enzymology, Podocytes/enzymology, Protein C/biosynthesis, Signal Transduction/genetics, Thrombomodulin/physiology",
author = "Berend Isermann and Vinnikov, {Ilya A} and Thati Madhusudhan and Stefanie Herzog and Muhammed Kashif and Janusch Blautzik and Corat, {Marcus A F} and Martin Zeier and Erwin Blessing and Jun Oh and Bruce Gerlitz and Berg, {David T} and Grinnell, {Brian W} and Triantafyllos Chavakis and Esmon, {Charles T} and Hartmut Weiler and Angelika Bierhaus and Nawroth, {Peter P}",
year = "2007",
month = nov,
doi = "10.1038/nm1667",
language = "English",
volume = "13",
pages = "1349--58",
journal = "NAT MED",
issn = "1078-8956",
publisher = "NATURE PUBLISHING GROUP",
number = "11",

}

RIS

TY - JOUR

T1 - Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis

AU - Isermann, Berend

AU - Vinnikov, Ilya A

AU - Madhusudhan, Thati

AU - Herzog, Stefanie

AU - Kashif, Muhammed

AU - Blautzik, Janusch

AU - Corat, Marcus A F

AU - Zeier, Martin

AU - Blessing, Erwin

AU - Oh, Jun

AU - Gerlitz, Bruce

AU - Berg, David T

AU - Grinnell, Brian W

AU - Chavakis, Triantafyllos

AU - Esmon, Charles T

AU - Weiler, Hartmut

AU - Bierhaus, Angelika

AU - Nawroth, Peter P

PY - 2007/11

Y1 - 2007/11

N2 - 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.

AB - 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.

KW - Amino Acid Substitution/genetics

KW - Animals

KW - Apoptosis/genetics

KW - Cell Line, Transformed

KW - Cells, Cultured

KW - Cytoprotection/genetics

KW - Diabetes Mellitus, Experimental/enzymology

KW - Diabetic Nephropathies/enzymology

KW - Endothelium, Vascular/enzymology

KW - Enzyme Activation/genetics

KW - Humans

KW - Kidney Glomerulus/blood supply

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Mutant Strains

KW - Mice, Transgenic

KW - Microcirculation/enzymology

KW - Podocytes/enzymology

KW - Protein C/biosynthesis

KW - Signal Transduction/genetics

KW - Thrombomodulin/physiology

U2 - 10.1038/nm1667

DO - 10.1038/nm1667

M3 - SCORING: Journal article

C2 - 17982464

VL - 13

SP - 1349

EP - 1358

JO - NAT MED

JF - NAT MED

SN - 1078-8956

IS - 11

ER -