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

Hongjie Wang; Ilya Vinnikov; Khurrum Shahzad; Fabian Bock; Satish Ranjan; Juliane Wolter; Muhammed Kashif; Jun Oh; Angelika Bierhaus; Peter Nawroth; Michael Kirschfink; Edward M. Conway; Thati Madhusudhan; Berend Isermann

doi:10.1160/TH12-07-0460

Thrombosis and Haemostasis, Inhaltsverzeichnis

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

¹Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany

²Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

,

Ilya Vinnikov

³Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany

,

Khurrum Shahzad

¹Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany

⁸University of Health Sciences, Khayaban-e-Jamia Punjab, Lahore, Pakistan

,

Fabian Bock

¹Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany

⁴Internal Medicine I and Clinical Chemistry, University of Heidelberg, INF 410, Heidelberg, Germany

,

Satish Ranjan

¹Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany

,

Juliane Wolter

¹Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany

,

Muhammed Kashif

⁴Internal Medicine I and Clinical Chemistry, University of Heidelberg, INF 410, Heidelberg, Germany

,

Jun Oh

⁵Department of Paediatric Nephrology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

,

Angelika Bierhaus

⁴Internal Medicine I and Clinical Chemistry, University of Heidelberg, INF 410, Heidelberg, Germany

,

Peter Nawroth

⁴Internal Medicine I and Clinical Chemistry, University of Heidelberg, INF 410, Heidelberg, Germany

,

Michael Kirschfink

⁶Institute of Immunology, University of Heidelberg, INF 305, Heidelberg, Germany

,

Edward M. Conway

⁷UBC Centre for Blood Research, Faculty of Medicine, Division of Haematology, Life Sciences Centre, Vancouver, British Columbia, Canada

,

Thati Madhusudhan

¹Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany

,

Berend Isermann

¹Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany

› Institutsangaben

Abstract

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 (TM^LeD/LeD) and controls (TM^wt/wt). Albuminuria (290 μg/mg vs. 166 μg/mg, p=0.03) and other indices of experimental diabetic nephropathy were aggravated in diabetic TM^LeD/LeDmice. Complement deposition (C3 and C5b-9) was markedly increased in glomeruli of diabetic TM^LeD/LeDmice. Complement inhibition with enoxaparin ameliorated diabetic nephropathy in TM^LeD/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 TM^LeD/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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Referenzen

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