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Dual antiplatelet and anticoagulant APAC prevents experimental ischemia–reperfusion-induced acute kidney injury

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Abstract

Background

Renal ischemia–reperfusion predisposes to acute kidney injury (AKI) and mortality. APAC, mast cell heparin proteoglycan mimetic is a potent dual antiplatelet and anticoagulant inhibiting thrombosis in several vascular models.

Methods

Clinically relevant (0.06 and 0.13 mg/kg) and high (0.32 and 7.3 mg/kg) heparin doses of APAC and unfractionated heparin (UFH) were administered i.v. in pharmacological studies. Antithrombotic action of APAC and UFH was assessed with platelet aggregation to collagen, activated partial thromboplastin (APTT) and prothrombin (PT) times. Pharmacodynamics of [64Cu]-APAC or -UFH were monitored by PET/CT. Next, APAC and UFH doses (0.06 and 0.13 mg/kg) were i.v. administered 10 min prior to renal ischemia–reperfusion injury (IRI) in rats.

Results

APAC in contrast to UFH inhibited platelet aggregation. During 0.06 and 0.13 mg/kg dose regimens APTT and PT remained at baseline, but at the high APTT prolonged fourfold to sixfold. Overall bio-distribution and clearance of APAC and UFH were similar. After bilateral 30-min renal artery clamping, creatinine, urea nitrogen and neutrophil gelatinase-associated lipocalin concentrations and histopathology indicated faster renal recovery by APAC (0.13 mg/kg). APAC, unlike UFH, prevented expression of innate immune ligand hyaluronan and tubulointerstitial injury marker Kim-1. Moreover, in severe bilateral 1-h renal artery clamping, APAC (0.13 mg/kg) prevented AKI, as demonstrated both by biomarkers and survival. Compatible with kidney protection APAC reduced the circulating levels of vascular destabilizing and pro-inflammatory angiopoietin-2 and syndecan-1. No tissue bleeding ensued.

Conclusion

APAC and UFH were similarly eliminated via kidneys and liver. In contrast to UFH, APAC (0.13 mg/kg) was reno-protective in moderate and even severe IRI by attenuating vascular injury and innate immune activation.

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Acknowledgments

We gratefully acknowledge biotechnician Marja Lemponen, HUSLAB Laboratory Services, Helsinki University Hospital, for her technical assistance throughout the experiments.

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Correspondence to Riitta Lassila.

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Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (University of Sherbrook Ethics protocol 372-14, Canada, and the State Provincial Office in Southern Finland, ESLH-2007-07748/Ym-23).

Conflict of interest

Employment: D. Salvail, C-E. Laurent and M-C. Benoit (IPS Therapeutique Inc., Sherbrooke, Canada). Stock ownership: R. Lassila, CSO and shareholder (Aplagon Oy, Helsinki, Finland). Research funding: R. Tuuminen, A. Jouppila, and S. Syrjälä (Aplagon Oy, Helsinki, Finland).

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Tuuminen, R., Jouppila, A., Salvail, D. et al. Dual antiplatelet and anticoagulant APAC prevents experimental ischemia–reperfusion-induced acute kidney injury. Clin Exp Nephrol 21, 436–445 (2017). https://doi.org/10.1007/s10157-016-1308-2

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  • DOI: https://doi.org/10.1007/s10157-016-1308-2

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