Cytoprotective signaling by activated protein C requires protease-activated receptor-3 in podocytes
The cytoprotective effects of activated protein C (aPC) are well established. In contrast, the receptors and signaling mechanism through which aPC conveys cytoprotection in various cell types remain incompletely defined. Thus, within the renal glomeruli, aPC preserves endothelial cells via a proteas...
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| Vydáno v: | Blood Ročník 119; číslo 3; s. 874 |
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| Hlavní autoři: | , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
19.01.2012
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| ISSN: | 1528-0020, 1528-0020 |
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| Abstract | The cytoprotective effects of activated protein C (aPC) are well established. In contrast, the receptors and signaling mechanism through which aPC conveys cytoprotection in various cell types remain incompletely defined. Thus, within the renal glomeruli, aPC preserves endothelial cells via a protease-activated receptor-1 (PAR-1) and endothelial protein C receptor-dependent mechanism. Conversely, the signaling mechanism through which aPC protects podocytes remains unknown. While exploring the latter, we identified a novel aPC/PAR-dependent cytoprotective signaling mechanism. In podocytes, aPC inhibits apoptosis through proteolytic activation of PAR-3 independent of endothelial protein C receptor. PAR-3 is not signaling competent itself as it requires aPC-induced heterodimerization with PAR-2 (human podocytes) or PAR-1 (mouse podocytes). This cytoprotective signaling mechanism depends on caveolin-1 dephosphorylation. In vivo aPC protects against lipopolysaccharide-induced podocyte injury and proteinuria. Genetic deletion of PAR-3 impairs the nephroprotective effect of aPC, demonstrating the crucial role of PAR-3 for aPC-dependent podocyte protection. This novel, aPC-mediated interaction of PARs demonstrates the plasticity and cell-specificity of cytoprotective aPC signaling. The evidence of specific, dynamic signaling complexes underlying aPC-mediated cytoprotection may allow the design of cell type specific targeted therapies. |
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| AbstractList | The cytoprotective effects of activated protein C (aPC) are well established. In contrast, the receptors and signaling mechanism through which aPC conveys cytoprotection in various cell types remain incompletely defined. Thus, within the renal glomeruli, aPC preserves endothelial cells via a protease-activated receptor-1 (PAR-1) and endothelial protein C receptor-dependent mechanism. Conversely, the signaling mechanism through which aPC protects podocytes remains unknown. While exploring the latter, we identified a novel aPC/PAR-dependent cytoprotective signaling mechanism. In podocytes, aPC inhibits apoptosis through proteolytic activation of PAR-3 independent of endothelial protein C receptor. PAR-3 is not signaling competent itself as it requires aPC-induced heterodimerization with PAR-2 (human podocytes) or PAR-1 (mouse podocytes). This cytoprotective signaling mechanism depends on caveolin-1 dephosphorylation. In vivo aPC protects against lipopolysaccharide-induced podocyte injury and proteinuria. Genetic deletion of PAR-3 impairs the nephroprotective effect of aPC, demonstrating the crucial role of PAR-3 for aPC-dependent podocyte protection. This novel, aPC-mediated interaction of PARs demonstrates the plasticity and cell-specificity of cytoprotective aPC signaling. The evidence of specific, dynamic signaling complexes underlying aPC-mediated cytoprotection may allow the design of cell type specific targeted therapies.The cytoprotective effects of activated protein C (aPC) are well established. In contrast, the receptors and signaling mechanism through which aPC conveys cytoprotection in various cell types remain incompletely defined. Thus, within the renal glomeruli, aPC preserves endothelial cells via a protease-activated receptor-1 (PAR-1) and endothelial protein C receptor-dependent mechanism. Conversely, the signaling mechanism through which aPC protects podocytes remains unknown. While exploring the latter, we identified a novel aPC/PAR-dependent cytoprotective signaling mechanism. In podocytes, aPC inhibits apoptosis through proteolytic activation of PAR-3 independent of endothelial protein C receptor. PAR-3 is not signaling competent itself as it requires aPC-induced heterodimerization with PAR-2 (human podocytes) or PAR-1 (mouse podocytes). This cytoprotective signaling mechanism depends on caveolin-1 dephosphorylation. In vivo aPC protects against lipopolysaccharide-induced podocyte injury and proteinuria. Genetic deletion of PAR-3 impairs the nephroprotective effect of aPC, demonstrating the crucial role of PAR-3 for aPC-dependent podocyte protection. This novel, aPC-mediated interaction of PARs demonstrates the plasticity and cell-specificity of cytoprotective aPC signaling. The evidence of specific, dynamic signaling complexes underlying aPC-mediated cytoprotection may allow the design of cell type specific targeted therapies. The cytoprotective effects of activated protein C (aPC) are well established. In contrast, the receptors and signaling mechanism through which aPC conveys cytoprotection in various cell types remain incompletely defined. Thus, within the renal glomeruli, aPC preserves endothelial cells via a protease-activated receptor-1 (PAR-1) and endothelial protein C receptor-dependent mechanism. Conversely, the signaling mechanism through which aPC protects podocytes remains unknown. While exploring the latter, we identified a novel aPC/PAR-dependent cytoprotective signaling mechanism. In podocytes, aPC inhibits apoptosis through proteolytic activation of PAR-3 independent of endothelial protein C receptor. PAR-3 is not signaling competent itself as it requires aPC-induced heterodimerization with PAR-2 (human podocytes) or PAR-1 (mouse podocytes). This cytoprotective signaling mechanism depends on caveolin-1 dephosphorylation. In vivo aPC protects against lipopolysaccharide-induced podocyte injury and proteinuria. Genetic deletion of PAR-3 impairs the nephroprotective effect of aPC, demonstrating the crucial role of PAR-3 for aPC-dependent podocyte protection. This novel, aPC-mediated interaction of PARs demonstrates the plasticity and cell-specificity of cytoprotective aPC signaling. The evidence of specific, dynamic signaling complexes underlying aPC-mediated cytoprotection may allow the design of cell type specific targeted therapies. |
| Author | Madhusudhan, Thati Schwenger, Vedat Reiser, Jochen Isermann, Berend Zhou, Qianxing Müller-Krebs, Sandra Gröne, Hermann-Josef Straub, Beate K Griffin, John H Wang, Hongjie Shahzad, Khurrum Nawroth, Peter P Grinnell, Brian W Gröne, Elisabeth Gerlitz, Bruce Esmon, Charles T |
| Author_xml | – sequence: 1 givenname: Thati surname: Madhusudhan fullname: Madhusudhan, Thati organization: Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Germany – sequence: 2 givenname: Hongjie surname: Wang fullname: Wang, Hongjie – sequence: 3 givenname: Beate K surname: Straub fullname: Straub, Beate K – sequence: 4 givenname: Elisabeth surname: Gröne fullname: Gröne, Elisabeth – sequence: 5 givenname: Qianxing surname: Zhou fullname: Zhou, Qianxing – sequence: 6 givenname: Khurrum surname: Shahzad fullname: Shahzad, Khurrum – sequence: 7 givenname: Sandra surname: Müller-Krebs fullname: Müller-Krebs, Sandra – sequence: 8 givenname: Vedat surname: Schwenger fullname: Schwenger, Vedat – sequence: 9 givenname: Bruce surname: Gerlitz fullname: Gerlitz, Bruce – sequence: 10 givenname: Brian W surname: Grinnell fullname: Grinnell, Brian W – sequence: 11 givenname: John H surname: Griffin fullname: Griffin, John H – sequence: 12 givenname: Jochen surname: Reiser fullname: Reiser, Jochen – sequence: 13 givenname: Hermann-Josef surname: Gröne fullname: Gröne, Hermann-Josef – sequence: 14 givenname: Charles T surname: Esmon fullname: Esmon, Charles T – sequence: 15 givenname: Peter P surname: Nawroth fullname: Nawroth, Peter P – sequence: 16 givenname: Berend surname: Isermann fullname: Isermann, Berend |
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| SubjectTerms | Animals Anticoagulants - metabolism Apoptosis Cell Communication Cells, Cultured Cytoprotection Humans Kidney Glomerulus - cytology Kidney Glomerulus - metabolism Lipopolysaccharides - pharmacology Membrane Microdomains Mice Podocytes - drug effects Podocytes - metabolism Podocytes - pathology Protein C - metabolism Protein Multimerization Receptor, PAR-1 - metabolism Receptors, Thrombin - metabolism Signal Transduction Thrombin |
| Title | Cytoprotective signaling by activated protein C requires protease-activated receptor-3 in podocytes |
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