Activated protein C protects against renal ischaemia/reperfusion injury, independent of its anticoagulant properties

Lionel Lattenist; Marcel P. B. Jansen; Gwendoline Teske; Nike Claessen; Joost C. M. Meijers; Alireza R. Rezaie; Charles T. Esmon; Sandrine Florquin; Joris J. T. H. Roelofs

doi:10.1160/TH15-07-0584

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 116(01): 124-133
DOI: 10.1160/TH15-07-0584

Blood Cells, Inflammation and Infection

Schattauer GmbH

Activated protein C protects against renal ischaemia/reperfusion injury, independent of its anticoagulant properties

Authors

Lionel Lattenist

¹Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Marcel P. B. Jansen

¹Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Gwendoline Teske

¹Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Nike Claessen

¹Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Joost C. M. Meijers

⁴Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, the Netherlands

⁵Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands
Alireza R. Rezaie

⁶Department of Biochemistry and Molecular Biology, St Louis University School of Medicine, St Louis, Missouri, USA
Charles T. Esmon

³Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
Sandrine Florquin

¹Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

²Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Joris J. T. H. Roelofs

¹Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Abstract

Summary

Acute renal failure, a serious condition characterised by a drastic decline in renal function, often follows ischaemia/reperfusion (I/R) episodes. I/R is characterised by necrosis, inflammation and activation of coagulation, in concert causing renal tissue damage. In this context, activated protein C (APC) might be of importance in the pathogenesis of renal I/R. APC is a serine protease which has anticoagulant but also several anti-inflammatory and cytoprotective effects such as protection of endothelial barrier function. It was our objective to study the role of cytoprotective and anticoagulant functions of APC during renal I/R. C57BL/6j mice subjected to renal I/R were treated with intraperitoneally injected exogenous human APC, or two mutant forms of APC(200 µg/kg) which specifically lack anticoagulant or signalling properties. In a different experiment mice received specific monoclonal antibodies (20 mg/kg) that block the cytoprotective and/or anticoagulant properties of endogenous APC. Treatment with APC reduced tubular injury and enhanced renal function without altering the inflammatory response and did reduce renal fibrin deposition. Administration of APC mutant lacking anticoagulant properties reduced renal damage and enhanced renal function. Blocking the anticoagulant and cytoprotective functions of endogenous APC resulted in elevated tubular damage and reduced tubular cell proliferation, however, without influencing renal function or the inflammatory response. Furthermore, blocking both the anticoagulant and cytoprotective effects of APC resulted in dramatic renal interstitial haemorrhage, indicative of impaired vascular integrity. Blocking only the anticoagulant function of APC did not result in interstitial bleeding. In conclusion, the renoprotective effect of APC during I/R is independent of its anticoagulant properties.

Keywords

Acute Kidney Injury - haemostasis - ischaemia-reperfusion injury - kidney - protein C

Full Text

References

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