title: Inhibition ofαvβ5 Integrin Attenuates Vascular Permeability and Protects against Renal Ischemia-Reperfusion Injury.
abstract: Ischemia-reperfusion injury (IRI) is a leading cause of AKI. This common clinical complication lacks effective therapies and can lead to the development of CKD. Theαvβ5 integrin may have an important role in acute injury, including septic shock and acute lung injury. To examine its function in AKI, we utilized a specific function-blocking antibody to inhibitαvβ5 in a rat model of renal IRI. Pretreatment with this anti-αvβ5 antibody significantly reduced serum creatinine levels, diminished renal damage detected by histopathologic evaluation, and decreased levels of injury biomarkers. Notably, therapeutic treatment with theαvβ5 antibody 8 hours after IRI also provided protection from injury. Global gene expression profiling of post-ischemic kidneys showed thatαvβ5 inhibition affected established injury markers and induced pathway alterations previously shown to be protective. Intravital imaging of post-ischemic kidneys revealed reduced vascular leak withαvβ5 antibody treatment. Immunostaining forαvβ5 in the kidney detected evident expression in perivascular cells, with negligible expression in the endothelium. Studies in a three-dimensional microfluidics system identified a pericyte-dependent role forαvβ5 in modulating vascular leak. Additional studies showedαvβ5 functions in the adhesion and migration of kidney pericytesin vitroInitial studies monitoring renal blood flow after IRI did not find significant effects withαvβ5 inhibition; however, future studies should explore the contribution of vasomotor effects. These studies identify a role forαvβ5 in modulating injury-induced renal vascular leak, possibly through effects on pericyte adhesion and migration, and revealαvβ5 inhibition as a promising therapeutic strategy for AKI.
authors.affiliation: Biogen Inc., Cambridge, Massachusetts; amy.mccurley@biogen.com.
authors.forename: Amy
authors.initials: A
authors.lastname: McCurley
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, Massachusetts.|The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, Massachusetts.
authors.forename: Stella
authors.initials: S
authors.lastname: Alimperti
authors.affiliation: Indiana University School of Medicine, The Roudebush Veterans Affair Medical Center, Indiana Center for Biological Microscopy, Indianapolis, Indiana; and.
authors.forename: Silvia B
authors.initials: SB
authors.lastname: Campos-Bilderback
authors.affiliation: Indiana University School of Medicine, The Roudebush Veterans Affair Medical Center, Indiana Center for Biological Microscopy, Indianapolis, Indiana; and.
authors.forename: Ruben M
authors.initials: RM
authors.lastname: Sandoval
authors.affiliation: Biogen Inc., Cambridge, Massachusetts.
authors.forename: Jenna E
authors.initials: JE
authors.lastname: Calvino
authors.affiliation: Biogen Inc., Cambridge, Massachusetts.
authors.forename: Taylor L
authors.initials: TL
authors.lastname: Reynolds
authors.affiliation: Biogen Inc., Cambridge, Massachusetts.
authors.forename: Catherine
authors.initials: C
authors.lastname: Quigley
authors.affiliation: Biogen Inc., Cambridge, Massachusetts.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Mugford
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, Massachusetts.|The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, Massachusetts.
authors.forename: William J
authors.initials: WJ
authors.lastname: Polacheck
authors.affiliation: Biogen Inc., Cambridge, Massachusetts.
authors.forename: Ivan G
authors.initials: IG
authors.lastname: Gomez
authors.affiliation: Biogen Inc., Cambridge, Massachusetts.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dovey
authors.affiliation: Biogen Inc., Cambridge, Massachusetts.
authors.forename: Graham
authors.initials: G
authors.lastname: Marsh
authors.affiliation: Biogen Inc., Cambridge, Massachusetts.
authors.forename: Angela
authors.initials: A
authors.lastname: Huang
authors.affiliation: Biogen Inc., Cambridge, Massachusetts.
authors.forename: Fang
authors.initials: F
authors.lastname: Qian
authors.affiliation: Biogen Inc., Cambridge, Massachusetts.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Weinreb
authors.affiliation: Biogen Inc., Cambridge, Massachusetts.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Dolinski
authors.affiliation: Biogen Inc., Cambridge, Massachusetts.
authors.forename: Shaun
authors.initials: S
authors.lastname: Moore
authors.affiliation: Biogen Inc., Cambridge, Massachusetts.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, Massachusetts.|The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, Massachusetts.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Indiana University School of Medicine, The Roudebush Veterans Affair Medical Center, Indiana Center for Biological Microscopy, Indianapolis, Indiana; and.|Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Molitoris
authors.affiliation: Biogen Inc., Cambridge, Massachusetts.
authors.forename: Shelia M
authors.initials: SM
authors.lastname: Violette
authors.affiliation: Biogen Inc., Cambridge, Massachusetts.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Crackower
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D007668:Kidney / Q000098:blood supply*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000517:prevention & control*
chemical_list: D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5
keywords: acute renal failure; adhesion molecule; renal ischemia; vascular