PMID- 27405618 OWN - NLM STAT- MEDLINE DCOM- 20180402 LR - 20220310 IS - 1437-7799 (Electronic) IS - 1342-1751 (Linking) VI - 21 IP - 3 DP - 2017 Jun TI - Dual antiplatelet and anticoagulant APAC prevents experimental ischemia-reperfusion-induced acute kidney injury. PG - 436-445 LID - 10.1007/s10157-016-1308-2 [doi] AB - 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 [(64)Cu]-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. FAU - Tuuminen, Raimo AU - Tuuminen R AD - Transplantation Laboratory Haartman Institute, University of Helsinki, Helsinki, Finland. AD - Department of Cardiothoracic Surgery, Helsinki University Hospital, Helsinki, Finland. FAU - Jouppila, Annukka AU - Jouppila A AD - Helsinki University Hospital Research Institute, Helsinki, Finland. FAU - Salvail, Dan AU - Salvail D AD - IPS Therapeutique, Sherbrooke, Canada. FAU - Laurent, Charles-E AU - Laurent CE AD - IPS Therapeutique, Sherbrooke, Canada. FAU - Benoit, Marie-Claude AU - Benoit MC AD - IPS Therapeutique, Sherbrooke, Canada. FAU - Syrjala, Simo AU - Syrjala S AD - Transplantation Laboratory Haartman Institute, University of Helsinki, Helsinki, Finland. AD - Department of Cardiothoracic Surgery, Helsinki University Hospital, Helsinki, Finland. FAU - Helin, Heikki AU - Helin H AD - Division of Pathology, HUSLAB and Helsinki University Hospital, Helsinki, Finland. FAU - Lemstrom, Karl AU - Lemstrom K AD - Transplantation Laboratory Haartman Institute, University of Helsinki, Helsinki, Finland. AD - Department of Cardiothoracic Surgery, Helsinki University Hospital, Helsinki, Finland. FAU - Lassila, Riitta AU - Lassila R AUID- ORCID: 0000-0003-4470-0650 AD - Coagulation Disorders Unit, University of Helsinki, Helsinki, Finland. riitta.lassila@hus.fi. AD - Departments of Hematology and Clinical Chemistry (HUSLAB Laboratory Services), Comprehensive Cancer Center, Helsinki University Central Hospital, PoB 372, 00029, Helsinki, Finland. riitta.lassila@hus.fi. LA - eng PT - Comparative Study PT - Journal Article DEP - 20160712 PL - Japan TA - Clin Exp Nephrol JT - Clinical and experimental nephrology JID - 9709923 RN - 0 (Acute-Phase Proteins) RN - 0 (Angiopoietin-2) RN - 0 (Anticoagulants) RN - 0 (Biomarkers) RN - 0 (Lcn2 protein, rat) RN - 0 (Lipocalin-2) RN - 0 (Lipocalins) RN - 0 (Platelet Aggregation Inhibitors) RN - 0 (Proteoglycans) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Syndecan-1) RN - 0 (heparin proteoglycan) RN - 9004-61-9 (Hyaluronic Acid) RN - 9005-49-6 (Heparin) RN - AYI8EX34EU (Creatinine) SB - IM MH - Acute Kidney Injury/blood/immunology/pathology/*prevention & control MH - Acute-Phase Proteins MH - Angiopoietin-2/blood MH - Animals MH - Anticoagulants/pharmacokinetics/*pharmacology MH - Biomarkers/blood MH - Biotransformation MH - Blood Coagulation/drug effects MH - Blood Urea Nitrogen MH - Creatinine/blood MH - Disease Models, Animal MH - Drug Therapy, Combination MH - Heparin/*analogs & derivatives/pharmacokinetics/*pharmacology MH - Hyaluronic Acid/blood MH - Immunity, Innate/drug effects MH - Kidney/*drug effects/immunology/metabolism/pathology MH - Lipocalin-2 MH - Lipocalins/blood MH - Male MH - Partial Thromboplastin Time MH - Platelet Aggregation/drug effects MH - Platelet Aggregation Inhibitors/pharmacokinetics/*pharmacology MH - Platelet Function Tests MH - Positron Emission Tomography Computed Tomography MH - Proteoglycans/pharmacokinetics/*pharmacology MH - Prothrombin Time MH - Proto-Oncogene Proteins/blood MH - Rats, Sprague-Dawley MH - Reperfusion Injury/blood/immunology/pathology/*prevention & control MH - Syndecan-1/blood MH - Tissue Distribution OTO - NOTNLM OT - APAC OT - Acute kidney injury OT - Ischemia-reperfusion injury OT - Unfractionated heparin EDAT- 2016/07/14 06:00 MHDA- 2018/04/03 06:00 CRDT- 2016/07/14 06:00 PHST- 2016/05/02 00:00 [received] PHST- 2016/07/06 00:00 [accepted] PHST- 2016/07/14 06:00 [pubmed] PHST- 2018/04/03 06:00 [medline] PHST- 2016/07/14 06:00 [entrez] AID - 10.1007/s10157-016-1308-2 [pii] AID - 10.1007/s10157-016-1308-2 [doi] PST - ppublish SO - Clin Exp Nephrol. 2017 Jun;21(3):436-445. doi: 10.1007/s10157-016-1308-2. Epub 2016 Jul 12.