title: The small fibrinopeptide Bβ15-42 as renoprotective agent preserving the endothelial and vascular integrity in early ischemia reperfusion injury in the mouse kidney.
abstract: Disruption of the renal endothelial integrity is pivotal for the development of a vascular leak, tissue edema and consequently acute kidney injury. Kidney ischemia amplifies endothelial activation and up-regulation of pro-inflammatory mechanisms. After restoring a sufficient blood flow, the kidney is damaged through complex pathomechanisms that are classically referred to as ischemia and reperfusion injury, where the disruption of the inter-endothelial connections seems to be a crucial step in this pathomechanism. Focusing on the molecular cell-cell interaction, the fibrinopeptide Bβ15-42 prevents vascular leakage by stabilizing these inter-endothelial junctions. The peptide associates with vascular endothelial-cadherin, thus preventing early kidney dysfunction by preserving blood perfusion efficacy, edema formation and thus organ dysfunction. We intended to demonstrate the early therapeutic benefit of intravenously administered Bβ15-42 in a mouse model of renal ischemia and reperfusion. After 30 minutes of ischemia, the fibrinopeptide Bβ15-42 was administered intravenously before reperfusion was commenced for 1 and 3 hours. We show that Bβ15-42 alleviates early functional and morphological kidney damage as soon as 1 h and 3 h after ischemia and reperfusion. Mice treated with Bβ15-42 displayed a significantly reduced loss of VE-cadherin, indicating a conserved endothelial barrier leading to less neutrophil infiltration which in turn resulted in significantly reduced structural renal damage. The significant reduction in tissue and serum neutrophil gelatinase-associated lipocalin levels reinforced our findings. Moreover, renal perfusion analysis by color duplex sonography revealed that Bβ15-42 treatment preserved resistive indices and even improved blood velocity. Our data demonstrate the efficacy of early therapeutic intervention using the fibrinopeptide Bβ15-42 in the treatment of acute kidney injury resulting from ischemia and reperfusion. In this context Bβ15-42 may act as a potent renoprotective agent by preserving the endothelial and vascular integrity.
authors.affiliation: Faculty of Medicine, Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Urbschat
authors.affiliation: Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Zacharowski
authors.affiliation: Clinic of Internal Medicine III, Division of Nephrology, Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Obermüller
authors.affiliation: Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Rupprecht
authors.affiliation: Institute of Cardiovascular Regeneration, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Penzkofer
authors.affiliation: Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Carla
authors.initials: C
authors.lastname: Jennewein
authors.affiliation: Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Nguyen
authors.initials: N
authors.lastname: Tran
authors.affiliation: Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Bertram
authors.initials: B
authors.lastname: Scheller
authors.affiliation: Institute of Cardiovascular Regeneration, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
authors.affiliation: Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Paulus
mesh_terms: D058186:Acute Kidney Injury / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000209:Acute-Phase Proteins / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects*; D005338:Fibrin Fibrinogen Degradation Products / Q000008:administration & dosage / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000187:drug effects*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000097:blood / Q000235:genetics; D008297:Male; D051379:Mice; D020556:Neutrophil Infiltration; D015513:Oncogene Proteins / Q000097:blood / Q000235:genetics; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D014463:Ultrasonography; D000099152:Cadherin 5
chemical_list: D000209:Acute-Phase Proteins; D015703:Antigens, CD; D015820:Cadherins; D005338:Fibrin Fibrinogen Degradation Products; D018799:Intercellular Adhesion Molecule-1; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D019007:P-Selectin; D010446:Peptide Fragments; D020011:Protective Agents; D019718:Receptors, CXCR4; D000099152:Cadherin 5; C033786:fibrinogen Bbeta (15-42); C071332:Lcn2 protein, mouse