Inhibition of α v β 5 Integrin Attenuates Vascular Permeability and Protects against Renal Ischemia-Reperfusion Injury

• Published in: Journal of the American Society of Nephrology Vol. 28; no. 6; p. 1741
• Main Authors: McCurley, Amy, Alimperti, Stella, Campos-Bilderback, Silvia B, Sandoval, Ruben M, Calvino, Jenna E, Reynolds, Taylor L, Quigley, Catherine, Mugford, Joshua W, Polacheck, William J, Gomez, Ivan G, Dovey, Jennifer, Marsh, Graham, Huang, Angela, Qian, Fang, Weinreb, Paul H, Dolinski, Brian M, Moore, Shaun, Duffield, Jeremy S, Chen, Christopher S, Molitoris, Bruce A, Violette, Shelia M, Crackower, Michael A
• Format: Journal Article
• Language: English
• Published: United States 01.06.2017
• Subjects: Animals; Capillary Permeability - drug effects; Kidney - blood supply; Male; Rats; Rats, Sprague-Dawley; Receptors, Vitronectin - antagonists & inhibitors; Reperfusion Injury - prevention & control; acute renal failure; renal ischemia; vascular; adhesion molecule
• ISSN: 1533-3450
• DOI: 10.1681/ASN.2016020200

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 v 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 v 5 in a rat model of renal IRI. Pretreatment with this anti- v 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 v 5 antibody 8 hours after IRI also provided protection from injury. Global gene expression profiling of post-ischemic kidneys showed that v 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 v 5 antibody treatment. Immunostaining for v 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 v 5 in modulating vascular leak. Additional studies showed v 5 functions in the adhesion and migration of kidney pericytes Initial studies monitoring renal blood flow after IRI did not find significant effects with v 5 inhibition; however, future studies should explore the contribution of vasomotor effects. These studies identify a role for v 5 in modulating injury-induced renal vascular leak, possibly through effects on pericyte adhesion and migration, and reveal v 5 inhibition as a promising therapeutic strategy for AKI.