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  • Review Article
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The emerging role of coagulation proteases in kidney disease

Nature Reviews Nephrology volume 12, pages 94–109 (2016)Cite this article

Subjects

Key Points

  • In addition to their pivotal and well-established functions in haemostasis, coagulation regulators and receptors mediate non-haemostatic functions in the kidney

  • Derangements of the coagulation system and altered coagulation-protease-dependent signalling in renal disease might alter disease progression

  • Coagulation proteases alter the function of a variety of renal cell types via distinct protease-activated receptors (PARs) and co-receptors

  • Activated protein C has nephroprotective effects that are at least partly independent of its anticoagulant function

  • The new drug classes of target-specific oral anticoagulants and PAR inhibitors might interfere with the functions of coagulation proteases in renal disease, with potential beneficial or adverse effects

Abstract

A role of coagulation proteases in kidney disease beyond their function in normal haemostasis and thrombosis has long been suspected, and studies performed in the past 15 years have provided novel insights into the mechanisms involved. The expression of protease-activated receptors (PARs) in renal cells provides a molecular link between coagulation proteases and renal cell function and revitalizes research evaluating the role of haemostasis regulators in renal disease. Renal cell-specific expression and activity of coagulation proteases, their regulators and their receptors are dynamically altered during disease processes. Furthermore, renal inflammation and tissue remodelling are not only associated, but are causally linked with altered coagulation activation and protease-dependent signalling. Intriguingly, coagulation proteases signal through more than one receptor or induce formation of receptor complexes in a cell-specific manner, emphasizing context specificity. Understanding these cell-specific signalosomes and their regulation in kidney disease is crucial to unravelling the pathophysiological relevance of coagulation regulators in renal disease. In addition, the clinical availability of small molecule targeted anticoagulants as well as the development of PAR antagonists increases the need for in-depth knowledge of the mechanisms through which coagulation proteases might regulate renal physiology.

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Figure 1: The coagulation system.
Figure 2: Initiation, amplification and propagation of coagulation.
Figure 3: Potential mechanisms of PAR activation by thrombin and aPC.
Figure 4: Expression of coagulation protease receptors in renal cells.
Figure 5: Coagulation regulators in acute kidney injury.
Figure 6: Coagulation regulators in chronic kidney injury.

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Acknowledgements

This work was supported by grants from the Deutsche Forschungsgemeinschaft (IS 67/2-4, IS-67/5-2, SFB 854 to B.I.; TH 1789/1-1 to T.M.), the Stiftung Pathobiochemie und Molekulare Diagnostik (B.I. and T.M.) and from the National Institutes of Health (U54-DK083912-05S1 and L40-DK103299m to B.A.K.).

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  1. Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke-University, Magdeburg, Leipziger Strasse 44, Magdeburg, D-39120, Germany

    Thati Madhusudhan & Berend Isermann

  2. Center for Clinical and Translational Research, Nationwide Children's Hospital, 700 Children's Drive, W325, Columbus, 43205, Ohio, USA

    Bryce A. Kerlin

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Madhusudhan, T., Kerlin, B. & Isermann, B. The emerging role of coagulation proteases in kidney disease. Nat Rev Nephrol 12, 94–109 (2016). https://doi.org/10.1038/nrneph.2015.177

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