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J Am Soc Nephrol. 2017 Jun;28(6):1741-1752. doi: 10.1681/ASN.2016020200. Epub 2017 Jan 6.

Inhibition of αvβ5 Integrin Attenuates Vascular Permeability and Protects against Renal Ischemia-Reperfusion Injury.

Author information

1
Biogen Inc., Cambridge, Massachusetts; amy.mccurley@biogen.com.
2
Department of Biomedical Engineering, Boston University, Boston, Massachusetts.
3
The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, Massachusetts.
4
Indiana University School of Medicine, The Roudebush Veterans Affair Medical Center, Indiana Center for Biological Microscopy, Indianapolis, Indiana; and.
5
Biogen Inc., Cambridge, Massachusetts.
6
Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana.

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. The αvβ5 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 inhibit αvβ5 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 the αvβ5 antibody 8 hours after IRI also provided protection from injury. Global gene expression profiling of post-ischemic kidneys showed that αvβ5 inhibition affected established injury markers and induced pathway alterations previously shown to be protective. Intravital imaging of post-ischemic kidneys revealed reduced vascular leak with αvβ5 antibody treatment. Immunostaining for αvβ5 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 for αvβ5 in modulating vascular leak. Additional studies showed αvβ5 functions in the adhesion and migration of kidney pericytes in vitro Initial studies monitoring renal blood flow after IRI did not find significant effects with αvβ5 inhibition; however, future studies should explore the contribution of vasomotor effects. These studies identify a role for αvβ5 in modulating injury-induced renal vascular leak, possibly through effects on pericyte adhesion and migration, and reveal αvβ5 inhibition as a promising therapeutic strategy for AKI.

KEYWORDS:

acute renal failure; adhesion molecule; renal ischemia; vascular

PMID:
28062569
PMCID:
PMC5461783
DOI:
10.1681/ASN.2016020200
[Indexed for MEDLINE]
Free PMC Article

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