Inhibition of αvβ5 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. The <i>α</i>v<i>β</i>5 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 <i>α</i>v<i>β</i>5 in a rat model of renal IRI. Pretreatment with this anti-<i>α</i>v<i>β</i>5 antibody significantly reduced serum creatinine levels, diminished renal damage detected by histopathologic evaluation, and decreased levels of injury biomarkers. Notably, therapeutic treatment with the <i>α</i>v<i>β</i>5 antibody 8 hours after IRI also provided protection from injury. Global gene expression profiling of post-ischemic kidneys showed that <i>α</i>v<i>β</i>5 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 <i>α</i>v<i>β</i>5 antibody treatment. Immunostaining for <i>α</i>v<i>β</i>5 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 <i>α</i>v<i>β</i>5 in modulating vascular leak. Additional studies showed <i>α</i>v<i>β</i>5 functions in the adhesion and migration of kidney pericytes <i>in vitro</i> Initial studies monitoring renal blood flow after IRI did not find significant effects with <i>α</i>v<i>β</i>5 inhibition; however, future studies should explore the contribution of vasomotor effects. These studies identify a role for <i>α</i>v<i>β</i>5 in modulating injury-induced renal vascular leak, possibly through effects on pericyte adhesion and migration, and reveal <i>α</i>v<i>β</i>5 inhibition as a promising therapeutic strategy for AKI.