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Inhibition of ?v?5 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 ?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 in vitro 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.

SUBMITTER: McCurley A

PROVIDER: S-EPMC5461783 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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

McCurley Amy A Alimperti Stella S Campos-Bilderback Silvia B SB Sandoval Ruben M RM Calvino Jenna E JE Reynolds Taylor L TL Quigley Catherine C Mugford Joshua W JW Polacheck William J WJ Gomez Ivan G IG Dovey Jennifer J Marsh Graham G Huang Angela A Qian Fang F Weinreb Paul H PH Dolinski Brian M BM Moore Shaun S Duffield Jeremy S JS Chen Christopher S CS Molitoris Bruce A BA Violette Shelia M SM Crackower Michael A MA

Journal of the American Society of Nephrology : JASN 20170106 6

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 reduce ...[more]

PMID: 28062569

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Project description:BackgroundMany retinal diseases are associated with vascular dysfunction accompanied by neuroinflammation. We examined the ability of minocycline (Mino), a tetracycline derivative with anti-inflammatory and neuroprotective properties, to prevent vascular permeability and inflammation following retinal ischemia-reperfusion (IR) injury, a model of retinal neurodegeneration with breakdown of the blood-retinal barrier (BRB).MethodsMale Sprague-Dawley rats were subjected to 45 min of pressure-induced retinal ischemia, with the contralateral eye serving as control. Rats were treated with Mino prior to and following IR. At 48 h after reperfusion, retinal gene expression, cellular inflammation, Evan's blue dye leakage, tight junction protein organization, caspase-3 activation, and DNA fragmentation were measured. Cellular inflammation was quantified by flow-cytometric evaluation of retinal tissue using the myeloid marker CD11b and leukocyte common antigen CD45 to differentiate and quantify CD11b+/CD45low microglia, CD11b+/CD45hi myeloid leukocytes and CD11bneg/CD45hi lymphocytes. Major histocompatibility complex class II (MHCII) immunoreactivity was used to determine the inflammatory state of these cells.ResultsMino treatment significantly inhibited IR-induced retinal vascular permeability and disruption of tight junction organization. Retinal IR injury significantly altered mRNA expression for 21 of 25 inflammation- and gliosis-related genes examined. Of these, Mino treatment effectively attenuated IR-induced expression of lipocalin 2 (LCN2), serpin peptidase inhibitor clade A member 3 N (SERPINA3N), TNF receptor superfamily member 12A (TNFRSF12A), monocyte chemoattractant-1 (MCP-1, CCL2) and intercellular adhesion molecule-1 (ICAM-1). A marked increase in leukostasis of both myeloid leukocytes and lymphocytes was observed following IR. Mino treatment significantly reduced retinal leukocyte numbers following IR and was particularly effective in decreasing the appearance of MHCII+ inflammatory leukocytes. Surprisingly, Mino did not significantly inhibit retinal cell death in this model.ConclusionsIR induces a retinal neuroinflammation within hours of reperfusion characterized by inflammatory gene expression, leukocyte adhesion and invasion, and vascular permeability. Despite Mino significantly inhibiting these responses, it failed to block neurodegeneration.

Dataset Information

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

Publications

Inhibition of <i>α</i>v<i>β</i>5 Integrin Attenuates Vascular Permeability and Protects against Renal Ischemia-Reperfusion Injury.

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