Inhibition of avb5 integrin attenuates vascular permeability and protects against renal ischemia-reperfusion injury

Amy McCurley, Stella Alimperti, Silvia Campos-Bilderback, Ruben M. Sandoval, Jenna E. Calvino, Taylor L. Reynolds, Catherine Quigley, Joshua W. Mugford, William J. Polacheck, Ivan G. Gomez, Jennifer Dovey, Graham Marsh, Angela Huang, Fang Qian, Paul H. Weinreb, Brian M. Dolinski, Shaun Moore, Jeremy S. Duffield, Christopher S. Chen, Bruce MolitorisShelia M. Violette, Michael A. Crackower

Research output: Contribution to journalArticle

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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 avb5 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 inhibitavb5 in a ratmodel of renal IRI. Pretreatment with this anti-Avb5antibodysignificantly reduced serumcreatinine levels, diminishedrenaldamagedetectedby histopathologic evaluation, anddecreased levelsof injury biomarkers. Notably, therapeutic treatment with the avb5 antibody 8 hours after IRI also provided protection from injury. Global gene expression profiling of post-ischemic kidneys showed that avb5 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 avb5 antibody treatment. Immunostaining for avb5 in the kidney detected evident expression in perivascular cells, with negligible expression in the endothelium. Studies in a three-dimensionalmicrofluidics system identified a pericyte-dependent role for avb5 in modulating vascular leak. Additional studies showed avb5 functions in the adhesion and migration of kidney pericytes in vitro. Initial studiesmonitoring renal blood flow after IRI did not find significant effects with avb5 inhibition; however, future studies should explore the contribution of vasomotor effects. These studies identify a role for avb5 in modulating injury-induced renal vascular leak, possibly through effects on pericyte adhesion and migration, and reveal avb5 inhibition as a promising therapeutic strategy for AKI.

Original languageEnglish (US)
Pages (from-to)1741-1752
Number of pages12
JournalJournal of the American Society of Nephrology
Volume28
Issue number6
DOIs
StatePublished - Jun 1 2017

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ASJC Scopus subject areas

  • Nephrology

Cite this

McCurley, A., Alimperti, S., Campos-Bilderback, S., Sandoval, R. M., Calvino, J. E., Reynolds, T. L., Quigley, C., Mugford, J. W., Polacheck, W. J., Gomez, I. G., Dovey, J., Marsh, G., Huang, A., Qian, F., Weinreb, P. H., Dolinski, B. M., Moore, S., Duffield, J. S., Chen, C. S., ... Crackower, M. A. (2017). Inhibition of avb5 integrin attenuates vascular permeability and protects against renal ischemia-reperfusion injury. Journal of the American Society of Nephrology, 28(6), 1741-1752. https://doi.org/10.1681/ASN.2016020200