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

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 alpha v beta 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 alpha v beta 5 in a rat model of renal IRI. Pretreatment with this anti-alpha v beta 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 alpha v beta 5 antibody 8 hours after IRI also provided protection from injury. Global gene expression profiling of post-ischemic kidneys showed that alpha v beta 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 alpha v beta 5 antibody treatment. Immunostaining for alpha v beta 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 alpha v beta 5 in modulating vascular leak. Additional studies showed alpha v beta 5 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 alpha v beta 5 inhibition; however, future studies should explore the contribution of vasomotor effects. These studies identify a role for alpha v beta 5 in modulating injury-induced renal vascular leak, possibly through effects on pericyte adhesion and migration, and reveal alpha v beta 5 inhibition as a promising therapeutic strategy for AKI.