The lectin-like domain of thrombomodulin ameliorates diabetic glomerulopathy via complement inhibition
Coagulation and complement regulators belong to two interactive systems constituting emerging mechanisms of diabetic nephropathy. Thrombomodulin (TM) regulates both coagulation and complement activation, in part through discrete domains. TM’s lectin like domain dampens complement activation, while i...
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| Veröffentlicht in: | Thrombosis and haemostasis 2012-12, Vol.108 (6), p.1141-1153 |
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| creator | Wang, Hongjie Vinnikov, Ilya Shahzad, Khurrum Bock, Fabian Ranjan, Satish Wolter, Juliane Kashif, Muhammed Oh, Jun Bierhaus, Angelika Nawroth, Peter Kirschfink, Michael Conway, Edward M. Madhusudhan, Thati Isermann, Berend |
| description | Coagulation and complement regulators belong to two interactive systems constituting emerging mechanisms of diabetic nephropathy. Thrombomodulin (TM) regulates both coagulation and complement activation, in part through discrete domains. TM’s lectin like domain dampens complement activation, while its EGF-like domains independently enhance activation of the anti-coagulant and cytoprotective serine protease protein C (PC). A protective effect of activated PC in diabetic nephropathy is established. We hypothesised that TM controls diabetic nephropathy independent of PC through its lectin-like domain by regulating complement. Diabetic nephropathy was analysed in mice lacking TM’s lectin-like domain (TMLeD/LeD) and controls (TMwt/wt). Albuminuria (290 μg/mg vs. 166 μg/mg, p=0.03) and other indices of experimental diabetic nephropathy were aggravated in diabetic TMLeD/LeD mice. Complement deposition (C3 and C5b-9) was markedly increased in glomeruli of diabetic TMLeD/LeD mice. Complement inhibition with enoxaparin ameliorated diabetic nephropathy in TMLeD/LeD mice (e.g. albuminuria 85 μg/mg vs. 290 μg/mg, p |
| doi_str_mv | 10.1160/th12-07-0460 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed_thiem</sourceid><recordid>TN_cdi_pubmed_primary_23014597</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>23014597</sourcerecordid><originalsourceid>FETCH-LOGICAL-c564t-4a547c11de76edb4b242bb7beef57c9017fa4c3f1d56e4bf798b00b07ccd42693</originalsourceid><addsrcrecordid>eNp1kE1v1DAQhi0EokvhxhnlwgkCduLYmyOqgCJV4rJI3KyxM8Eu_ohsp1X_PVntUk6cRjPzaEbvQ8hrRj8wJujHalnXUtlSLugTsusGIVuxH38-JTvac9qKjg8X5EUpt5QywcfhObnoesr4MModmQ8WG4-muth69xubKQVwsUlzU21OQaeQptVvEwjoXcpQsTSTA43VmeaXTwHz6tMC1T40dw4ak8LiMWCsjYvWaVddii_Jsxl8wVfnekl-fPl8uLpub75__Xb16aY1g-C15TBwaRibUAqcNNcd77SWGnEepBkpkzNw089sGgRyPctxrynVVBoz8U6M_SV5f7prciol46yW7ALkB8WoOupSh2vWKSrVUdeGvznhy6oDTo_wXz8b8PYMQDHg5wzRuPKPE2IzyvYb9-7EVeu27Oo2rTluQf_3Np7oYizUCivmx5Nn62X7AnFSFjCkUuHYmxTrpnVbZGPdHSpXyoqqLGgceBUgrsVkt1TF9t3AVbHpXtkafP8Ha4yvJg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>The lectin-like domain of thrombomodulin ameliorates diabetic glomerulopathy via complement inhibition</title><source>MEDLINE</source><source>Thieme Connect Journals</source><creator>Wang, Hongjie ; Vinnikov, Ilya ; Shahzad, Khurrum ; Bock, Fabian ; Ranjan, Satish ; Wolter, Juliane ; Kashif, Muhammed ; Oh, Jun ; Bierhaus, Angelika ; Nawroth, Peter ; Kirschfink, Michael ; Conway, Edward M. ; Madhusudhan, Thati ; Isermann, Berend</creator><creatorcontrib>Wang, Hongjie ; Vinnikov, Ilya ; Shahzad, Khurrum ; Bock, Fabian ; Ranjan, Satish ; Wolter, Juliane ; Kashif, Muhammed ; Oh, Jun ; Bierhaus, Angelika ; Nawroth, Peter ; Kirschfink, Michael ; Conway, Edward M. ; Madhusudhan, Thati ; Isermann, Berend</creatorcontrib><description>Coagulation and complement regulators belong to two interactive systems constituting emerging mechanisms of diabetic nephropathy. Thrombomodulin (TM) regulates both coagulation and complement activation, in part through discrete domains. TM’s lectin like domain dampens complement activation, while its EGF-like domains independently enhance activation of the anti-coagulant and cytoprotective serine protease protein C (PC). A protective effect of activated PC in diabetic nephropathy is established. We hypothesised that TM controls diabetic nephropathy independent of PC through its lectin-like domain by regulating complement. Diabetic nephropathy was analysed in mice lacking TM’s lectin-like domain (TMLeD/LeD) and controls (TMwt/wt). Albuminuria (290 μg/mg vs. 166 μg/mg, p=0.03) and other indices of experimental diabetic nephropathy were aggravated in diabetic TMLeD/LeD mice. Complement deposition (C3 and C5b-9) was markedly increased in glomeruli of diabetic TMLeD/LeD mice. Complement inhibition with enoxaparin ameliorated diabetic nephropathy in TMLeD/LeD mice (e.g. albuminuria 85 μg/mg vs. 290 μg/mg, p<0.001). In vitro TM’s lectin-like domain cell-autonomously prevented glucose-induced complement activation on endothelial cells and – notably – on podocytes. Podocyte injury, which was enhanced in diabetic TMLeD/LeD mice, was reduced following complement inhibition with enoxaparin. The current study identifies a novel mechanism regulating complement activation in diabetic nephropathy. TM’s lectin-like domain constrains glucose-induced complement activation on endothelial cells and podocytes and ameliorates albuminuria and glomerular damage in mice.</description><identifier>ISSN: 0340-6245</identifier><identifier>EISSN: 2567-689X</identifier><identifier>DOI: 10.1160/th12-07-0460</identifier><identifier>PMID: 23014597</identifier><identifier>CODEN: THHADQ</identifier><language>eng</language><publisher>Stuttgart: Schattauer Verlag für Medizin und Naturwissenschaften</publisher><subject>Animals ; Biological and medical sciences ; Blood Coagulation, Fibrinolysis and Cellular Haemostasis ; Blood coagulation. Blood cells ; Cell Line ; complement ; Complement Activation - physiology ; Complement Inactivator Proteins - chemistry ; Complement Inactivator Proteins - deficiency ; Complement Inactivator Proteins - genetics ; Complement Inactivator Proteins - physiology ; Diabetes Mellitus, Experimental - complications ; Diabetes Mellitus, Experimental - immunology ; Diabetes Mellitus, Experimental - physiopathology ; Diabetes. Impaired glucose tolerance ; Diabetic Nephropathies - etiology ; Diabetic Nephropathies - physiopathology ; Diabetic Nephropathies - prevention & control ; diabetic nephropathy ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Endothelial Cells - immunology ; Endothelial Cells - pathology ; Endothelial Cells - physiology ; Endothelial dysfunction ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Fundamental and applied biological sciences. Psychology ; Hematologic and hematopoietic diseases ; Kidney Glomerulus - immunology ; Kidney Glomerulus - pathology ; Kidney Glomerulus - physiopathology ; Kidneys ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Molecular and cellular biology ; Nephrology. Urinary tract diseases ; Peptide Fragments - chemistry ; Peptide Fragments - genetics ; Peptide Fragments - physiology ; Platelet diseases and coagulopathies ; podocyte ; Podocytes - immunology ; Podocytes - pathology ; Podocytes - physiology ; Protein Structure, Tertiary ; Recombinant Proteins - chemistry ; Recombinant Proteins - genetics ; Recombinant Proteins - metabolism ; thrombomodulin ; Thrombomodulin - chemistry ; Thrombomodulin - deficiency ; Thrombomodulin - genetics ; Thrombomodulin - physiology ; Urinary system involvement in other diseases. Miscellaneous</subject><ispartof>Thrombosis and haemostasis, 2012-12, Vol.108 (6), p.1141-1153</ispartof><rights>2014 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c564t-4a547c11de76edb4b242bb7beef57c9017fa4c3f1d56e4bf798b00b07ccd42693</citedby><cites>FETCH-LOGICAL-c564t-4a547c11de76edb4b242bb7beef57c9017fa4c3f1d56e4bf798b00b07ccd42693</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.schattauer.de/typo3temp/pics/cover-1607_5f00be8808.jpg</thumbnail><linktopdf>$$Uhttps://www.thieme-connect.de/products/ejournals/pdf/10.1160/TH12-07-0460.pdf$$EPDF$$P50$$Gthieme$$H</linktopdf><linktohtml>$$Uhttps://www.thieme-connect.de/products/ejournals/html/10.1160/TH12-07-0460$$EHTML$$P50$$Gthieme$$H</linktohtml><link.rule.ids>314,778,782,3007,27911,27912,54546,54547</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26664918$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23014597$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Hongjie</creatorcontrib><creatorcontrib>Vinnikov, Ilya</creatorcontrib><creatorcontrib>Shahzad, Khurrum</creatorcontrib><creatorcontrib>Bock, Fabian</creatorcontrib><creatorcontrib>Ranjan, Satish</creatorcontrib><creatorcontrib>Wolter, Juliane</creatorcontrib><creatorcontrib>Kashif, Muhammed</creatorcontrib><creatorcontrib>Oh, Jun</creatorcontrib><creatorcontrib>Bierhaus, Angelika</creatorcontrib><creatorcontrib>Nawroth, Peter</creatorcontrib><creatorcontrib>Kirschfink, Michael</creatorcontrib><creatorcontrib>Conway, Edward M.</creatorcontrib><creatorcontrib>Madhusudhan, Thati</creatorcontrib><creatorcontrib>Isermann, Berend</creatorcontrib><title>The lectin-like domain of thrombomodulin ameliorates diabetic glomerulopathy via complement inhibition</title><title>Thrombosis and haemostasis</title><addtitle>Thromb Haemost</addtitle><description>Coagulation and complement regulators belong to two interactive systems constituting emerging mechanisms of diabetic nephropathy. Thrombomodulin (TM) regulates both coagulation and complement activation, in part through discrete domains. TM’s lectin like domain dampens complement activation, while its EGF-like domains independently enhance activation of the anti-coagulant and cytoprotective serine protease protein C (PC). A protective effect of activated PC in diabetic nephropathy is established. We hypothesised that TM controls diabetic nephropathy independent of PC through its lectin-like domain by regulating complement. Diabetic nephropathy was analysed in mice lacking TM’s lectin-like domain (TMLeD/LeD) and controls (TMwt/wt). Albuminuria (290 μg/mg vs. 166 μg/mg, p=0.03) and other indices of experimental diabetic nephropathy were aggravated in diabetic TMLeD/LeD mice. Complement deposition (C3 and C5b-9) was markedly increased in glomeruli of diabetic TMLeD/LeD mice. Complement inhibition with enoxaparin ameliorated diabetic nephropathy in TMLeD/LeD mice (e.g. albuminuria 85 μg/mg vs. 290 μg/mg, p<0.001). In vitro TM’s lectin-like domain cell-autonomously prevented glucose-induced complement activation on endothelial cells and – notably – on podocytes. Podocyte injury, which was enhanced in diabetic TMLeD/LeD mice, was reduced following complement inhibition with enoxaparin. The current study identifies a novel mechanism regulating complement activation in diabetic nephropathy. TM’s lectin-like domain constrains glucose-induced complement activation on endothelial cells and podocytes and ameliorates albuminuria and glomerular damage in mice.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blood Coagulation, Fibrinolysis and Cellular Haemostasis</subject><subject>Blood coagulation. Blood cells</subject><subject>Cell Line</subject><subject>complement</subject><subject>Complement Activation - physiology</subject><subject>Complement Inactivator Proteins - chemistry</subject><subject>Complement Inactivator Proteins - deficiency</subject><subject>Complement Inactivator Proteins - genetics</subject><subject>Complement Inactivator Proteins - physiology</subject><subject>Diabetes Mellitus, Experimental - complications</subject><subject>Diabetes Mellitus, Experimental - immunology</subject><subject>Diabetes Mellitus, Experimental - physiopathology</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Diabetic Nephropathies - etiology</subject><subject>Diabetic Nephropathies - physiopathology</subject><subject>Diabetic Nephropathies - prevention & control</subject><subject>diabetic nephropathy</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Endothelial Cells - immunology</subject><subject>Endothelial Cells - pathology</subject><subject>Endothelial Cells - physiology</subject><subject>Endothelial dysfunction</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Kidney Glomerulus - immunology</subject><subject>Kidney Glomerulus - pathology</subject><subject>Kidney Glomerulus - physiopathology</subject><subject>Kidneys</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Molecular and cellular biology</subject><subject>Nephrology. Urinary tract diseases</subject><subject>Peptide Fragments - chemistry</subject><subject>Peptide Fragments - genetics</subject><subject>Peptide Fragments - physiology</subject><subject>Platelet diseases and coagulopathies</subject><subject>podocyte</subject><subject>Podocytes - immunology</subject><subject>Podocytes - pathology</subject><subject>Podocytes - physiology</subject><subject>Protein Structure, Tertiary</subject><subject>Recombinant Proteins - chemistry</subject><subject>Recombinant Proteins - genetics</subject><subject>Recombinant Proteins - metabolism</subject><subject>thrombomodulin</subject><subject>Thrombomodulin - chemistry</subject><subject>Thrombomodulin - deficiency</subject><subject>Thrombomodulin - genetics</subject><subject>Thrombomodulin - physiology</subject><subject>Urinary system involvement in other diseases. Miscellaneous</subject><issn>0340-6245</issn><issn>2567-689X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kE1v1DAQhi0EokvhxhnlwgkCduLYmyOqgCJV4rJI3KyxM8Eu_ohsp1X_PVntUk6cRjPzaEbvQ8hrRj8wJujHalnXUtlSLugTsusGIVuxH38-JTvac9qKjg8X5EUpt5QywcfhObnoesr4MModmQ8WG4-muth69xubKQVwsUlzU21OQaeQptVvEwjoXcpQsTSTA43VmeaXTwHz6tMC1T40dw4ak8LiMWCsjYvWaVddii_Jsxl8wVfnekl-fPl8uLpub75__Xb16aY1g-C15TBwaRibUAqcNNcd77SWGnEepBkpkzNw089sGgRyPctxrynVVBoz8U6M_SV5f7prciol46yW7ALkB8WoOupSh2vWKSrVUdeGvznhy6oDTo_wXz8b8PYMQDHg5wzRuPKPE2IzyvYb9-7EVeu27Oo2rTluQf_3Np7oYizUCivmx5Nn62X7AnFSFjCkUuHYmxTrpnVbZGPdHSpXyoqqLGgceBUgrsVkt1TF9t3AVbHpXtkafP8Ha4yvJg</recordid><startdate>20121201</startdate><enddate>20121201</enddate><creator>Wang, Hongjie</creator><creator>Vinnikov, Ilya</creator><creator>Shahzad, Khurrum</creator><creator>Bock, Fabian</creator><creator>Ranjan, Satish</creator><creator>Wolter, Juliane</creator><creator>Kashif, Muhammed</creator><creator>Oh, Jun</creator><creator>Bierhaus, Angelika</creator><creator>Nawroth, Peter</creator><creator>Kirschfink, Michael</creator><creator>Conway, Edward M.</creator><creator>Madhusudhan, Thati</creator><creator>Isermann, Berend</creator><general>Schattauer Verlag für Medizin und Naturwissenschaften</general><general>Schattauer GmbH</general><general>Schattauer</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20121201</creationdate><title>The lectin-like domain of thrombomodulin ameliorates diabetic glomerulopathy via complement inhibition</title><author>Wang, Hongjie ; Vinnikov, Ilya ; Shahzad, Khurrum ; Bock, Fabian ; Ranjan, Satish ; Wolter, Juliane ; Kashif, Muhammed ; Oh, Jun ; Bierhaus, Angelika ; Nawroth, Peter ; Kirschfink, Michael ; Conway, Edward M. ; Madhusudhan, Thati ; Isermann, Berend</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c564t-4a547c11de76edb4b242bb7beef57c9017fa4c3f1d56e4bf798b00b07ccd42693</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blood Coagulation, Fibrinolysis and Cellular Haemostasis</topic><topic>Blood coagulation. Blood cells</topic><topic>Cell Line</topic><topic>complement</topic><topic>Complement Activation - physiology</topic><topic>Complement Inactivator Proteins - chemistry</topic><topic>Complement Inactivator Proteins - deficiency</topic><topic>Complement Inactivator Proteins - genetics</topic><topic>Complement Inactivator Proteins - physiology</topic><topic>Diabetes Mellitus, Experimental - complications</topic><topic>Diabetes Mellitus, Experimental - immunology</topic><topic>Diabetes Mellitus, Experimental - physiopathology</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Diabetic Nephropathies - etiology</topic><topic>Diabetic Nephropathies - physiopathology</topic><topic>Diabetic Nephropathies - prevention & control</topic><topic>diabetic nephropathy</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Endothelial Cells - immunology</topic><topic>Endothelial Cells - pathology</topic><topic>Endothelial Cells - physiology</topic><topic>Endothelial dysfunction</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Kidney Glomerulus - immunology</topic><topic>Kidney Glomerulus - pathology</topic><topic>Kidney Glomerulus - physiopathology</topic><topic>Kidneys</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Molecular and cellular biology</topic><topic>Nephrology. Urinary tract diseases</topic><topic>Peptide Fragments - chemistry</topic><topic>Peptide Fragments - genetics</topic><topic>Peptide Fragments - physiology</topic><topic>Platelet diseases and coagulopathies</topic><topic>podocyte</topic><topic>Podocytes - immunology</topic><topic>Podocytes - pathology</topic><topic>Podocytes - physiology</topic><topic>Protein Structure, Tertiary</topic><topic>Recombinant Proteins - chemistry</topic><topic>Recombinant Proteins - genetics</topic><topic>Recombinant Proteins - metabolism</topic><topic>thrombomodulin</topic><topic>Thrombomodulin - chemistry</topic><topic>Thrombomodulin - deficiency</topic><topic>Thrombomodulin - genetics</topic><topic>Thrombomodulin - physiology</topic><topic>Urinary system involvement in other diseases. Miscellaneous</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Hongjie</creatorcontrib><creatorcontrib>Vinnikov, Ilya</creatorcontrib><creatorcontrib>Shahzad, Khurrum</creatorcontrib><creatorcontrib>Bock, Fabian</creatorcontrib><creatorcontrib>Ranjan, Satish</creatorcontrib><creatorcontrib>Wolter, Juliane</creatorcontrib><creatorcontrib>Kashif, Muhammed</creatorcontrib><creatorcontrib>Oh, Jun</creatorcontrib><creatorcontrib>Bierhaus, Angelika</creatorcontrib><creatorcontrib>Nawroth, Peter</creatorcontrib><creatorcontrib>Kirschfink, Michael</creatorcontrib><creatorcontrib>Conway, Edward M.</creatorcontrib><creatorcontrib>Madhusudhan, Thati</creatorcontrib><creatorcontrib>Isermann, Berend</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Thrombosis and haemostasis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Hongjie</au><au>Vinnikov, Ilya</au><au>Shahzad, Khurrum</au><au>Bock, Fabian</au><au>Ranjan, Satish</au><au>Wolter, Juliane</au><au>Kashif, Muhammed</au><au>Oh, Jun</au><au>Bierhaus, Angelika</au><au>Nawroth, Peter</au><au>Kirschfink, Michael</au><au>Conway, Edward M.</au><au>Madhusudhan, Thati</au><au>Isermann, Berend</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The lectin-like domain of thrombomodulin ameliorates diabetic glomerulopathy via complement inhibition</atitle><jtitle>Thrombosis and haemostasis</jtitle><addtitle>Thromb Haemost</addtitle><date>2012-12-01</date><risdate>2012</risdate><volume>108</volume><issue>6</issue><spage>1141</spage><epage>1153</epage><pages>1141-1153</pages><issn>0340-6245</issn><eissn>2567-689X</eissn><coden>THHADQ</coden><abstract>Coagulation and complement regulators belong to two interactive systems constituting emerging mechanisms of diabetic nephropathy. Thrombomodulin (TM) regulates both coagulation and complement activation, in part through discrete domains. TM’s lectin like domain dampens complement activation, while its EGF-like domains independently enhance activation of the anti-coagulant and cytoprotective serine protease protein C (PC). A protective effect of activated PC in diabetic nephropathy is established. We hypothesised that TM controls diabetic nephropathy independent of PC through its lectin-like domain by regulating complement. Diabetic nephropathy was analysed in mice lacking TM’s lectin-like domain (TMLeD/LeD) and controls (TMwt/wt). Albuminuria (290 μg/mg vs. 166 μg/mg, p=0.03) and other indices of experimental diabetic nephropathy were aggravated in diabetic TMLeD/LeD mice. Complement deposition (C3 and C5b-9) was markedly increased in glomeruli of diabetic TMLeD/LeD mice. Complement inhibition with enoxaparin ameliorated diabetic nephropathy in TMLeD/LeD mice (e.g. albuminuria 85 μg/mg vs. 290 μg/mg, p<0.001). In vitro TM’s lectin-like domain cell-autonomously prevented glucose-induced complement activation on endothelial cells and – notably – on podocytes. Podocyte injury, which was enhanced in diabetic TMLeD/LeD mice, was reduced following complement inhibition with enoxaparin. The current study identifies a novel mechanism regulating complement activation in diabetic nephropathy. TM’s lectin-like domain constrains glucose-induced complement activation on endothelial cells and podocytes and ameliorates albuminuria and glomerular damage in mice.</abstract><cop>Stuttgart</cop><pub>Schattauer Verlag für Medizin und Naturwissenschaften</pub><pmid>23014597</pmid><doi>10.1160/th12-07-0460</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0340-6245 |
| ispartof | Thrombosis and haemostasis, 2012-12, Vol.108 (6), p.1141-1153 |
| issn | 0340-6245 2567-689X |
| language | eng |
| recordid | cdi_pubmed_primary_23014597 |
| source | MEDLINE; Thieme Connect Journals |
| subjects | Animals Biological and medical sciences Blood Coagulation, Fibrinolysis and Cellular Haemostasis Blood coagulation. Blood cells Cell Line complement Complement Activation - physiology Complement Inactivator Proteins - chemistry Complement Inactivator Proteins - deficiency Complement Inactivator Proteins - genetics Complement Inactivator Proteins - physiology Diabetes Mellitus, Experimental - complications Diabetes Mellitus, Experimental - immunology Diabetes Mellitus, Experimental - physiopathology Diabetes. Impaired glucose tolerance Diabetic Nephropathies - etiology Diabetic Nephropathies - physiopathology Diabetic Nephropathies - prevention & control diabetic nephropathy Endocrine pancreas. Apud cells (diseases) Endocrinopathies Endothelial Cells - immunology Endothelial Cells - pathology Endothelial Cells - physiology Endothelial dysfunction Etiopathogenesis. Screening. Investigations. Target tissue resistance Fundamental and applied biological sciences. Psychology Hematologic and hematopoietic diseases Kidney Glomerulus - immunology Kidney Glomerulus - pathology Kidney Glomerulus - physiopathology Kidneys Medical sciences Mice Mice, Inbred C57BL Mice, Knockout Molecular and cellular biology Nephrology. Urinary tract diseases Peptide Fragments - chemistry Peptide Fragments - genetics Peptide Fragments - physiology Platelet diseases and coagulopathies podocyte Podocytes - immunology Podocytes - pathology Podocytes - physiology Protein Structure, Tertiary Recombinant Proteins - chemistry Recombinant Proteins - genetics Recombinant Proteins - metabolism thrombomodulin Thrombomodulin - chemistry Thrombomodulin - deficiency Thrombomodulin - genetics Thrombomodulin - physiology Urinary system involvement in other diseases. Miscellaneous |
| title | The lectin-like domain of thrombomodulin ameliorates diabetic glomerulopathy via complement inhibition |
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