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Thromb Haemost 2012; 108(06): 1141-1153
DOI: 10.1160/TH12-07-0460
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

The lectin-like domain of thrombomodulin ameliorates diabetic glomerulopathy via complement inhibition

Hongjie Wang
1   Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
2   Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
,
Ilya Vinnikov
3   Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany
,
Khurrum Shahzad
1   Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
8   University of Health Sciences, Khayaban-e-Jamia Punjab, Lahore, Pakistan
,
Fabian Bock
1   Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
4   Internal Medicine I and Clinical Chemistry, University of Heidelberg, INF 410, Heidelberg, Germany
,
Satish Ranjan
1   Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
,
Juliane Wolter
1   Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
,
Muhammed Kashif
4   Internal Medicine I and Clinical Chemistry, University of Heidelberg, INF 410, Heidelberg, Germany
,
Jun Oh
5   Department of Paediatric Nephrology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
Angelika Bierhaus
4   Internal Medicine I and Clinical Chemistry, University of Heidelberg, INF 410, Heidelberg, Germany
,
Peter Nawroth
4   Internal Medicine I and Clinical Chemistry, University of Heidelberg, INF 410, Heidelberg, Germany
,
Michael Kirschfink
6   Institute of Immunology, University of Heidelberg, INF 305, Heidelberg, Germany
,
Edward M. Conway
7   UBC Centre for Blood Research, Faculty of Medicine, Division of Haematology, Life Sciences Centre, Vancouver, British Columbia, Canada
,
Thati Madhusudhan
1   Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
,
Berend Isermann
1   Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
› Author Affiliations
Further Information

Publication History

Received: 03 July 2012

Accepted after minor revision: 28 August 2012

Publication Date:
30 November 2017 (online)

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Summary

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 anticoagulant 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/LeDmice. Complement deposition (C3 and C5b-9) was markedly increased in glomeruli of diabetic TMLeD/LeDmice. Complement inhibition with enoxaparin ameliorated diabetic nephropathy in TMLeD/LeDmice (e.g. albuminuria 85 μg/mg vs. 290 μg/mg, p <0.001). In vitroTM’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/LeDmice, 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.

Keywords

Thrombomodulin - complement - endothelial dysfunction - podocyte - diabetic nephropathy

 

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