title: Slit2 prevents neutrophil recruitment and renal ischemia-reperfusion injury.
abstract: Neutrophils recruited to the postischemic kidney contribute to the pathogenesis of ischemia-reperfusion injury (IRI), which is the most common cause of renal failure among hospitalized patients. The Slit family of secreted proteins inhibits chemotaxis of leukocytes by preventing activation of Rho-family GTPases, suggesting that members of this family might modulate the recruitment of neutrophils and the resulting IRI. Here, in static and microfluidic shear assays, Slit2 inhibited multiple steps required for the infiltration of neutrophils into tissue. Specifically, Slit2 blocked the capture and firm adhesion of human neutrophils to inflamed vascular endothelial barriers as well as their subsequent transmigration. To examine whether these observations were relevant to renal IRI, we administered Slit2 to mice before bilateral clamping of the renal pedicles. Assessed at 18 hours after reperfusion, Slit2 significantly inhibited renal tubular necrosis, neutrophil and macrophage infiltration, and rise in plasma creatinine. In vitro, Slit2 did not impair the protective functions of neutrophils, including phagocytosis and superoxide production, and did not inhibit neutrophils from killing the extracellular pathogen Staphylococcus aureus. In vivo, administration of Slit2 did not attenuate neutrophil recruitment or bacterial clearance in mice with ascending Escherichia coli urinary tract infections and did not increase the bacterial load in the livers of mice infected with the intracellular pathogen Listeria monocytogenes. Collectively, these results suggest that Slit2 may hold promise as a strategy to combat renal IRI without compromising the protective innate immune response.
authors.affiliation: Division of Nephrology, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Swasti
authors.initials: S
authors.lastname: Chaturvedi
authors.forename: Darren A
authors.initials: DA
authors.lastname: Yuen
authors.forename: Amandeep
authors.initials: A
authors.lastname: Bajwa
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Huang
authors.forename: Christiane
authors.initials: C
authors.lastname: Sokollik
authors.forename: Liping
authors.initials: L
authors.lastname: Huang
authors.forename: Grace Y
authors.initials: GY
authors.lastname: Lam
authors.forename: Soumitra
authors.initials: S
authors.lastname: Tole
authors.forename: Guang-Ying
authors.initials: GY
authors.lastname: Liu
authors.forename: Jerry
authors.initials: J
authors.lastname: Pan
authors.forename: Lauren
authors.initials: L
authors.lastname: Chan
authors.forename: Yaro
authors.initials: Y
authors.lastname: Sokolskyy
authors.forename: Manoj
authors.initials: M
authors.lastname: Puthia
authors.forename: Gabriela
authors.initials: G
authors.lastname: Godaly
authors.forename: Rohan
authors.initials: R
authors.lastname: John
authors.forename: Changsen
authors.initials: C
authors.lastname: Wang
authors.forename: Warren L
authors.initials: WL
authors.lastname: Lee
authors.forename: John H
authors.initials: JH
authors.lastname: Brumell
authors.forename: Mark D
authors.initials: MD
authors.lastname: Okusa
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Robinson
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D000818:Animals; D003404:Creatinine / Q000097:blood*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage* / Q000502:physiology; D007668:Kidney / Q000098:blood supply* / Q000276:immunology / Q000473:pathology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000008:administration & dosage* / Q000502:physiology; D020556:Neutrophil Infiltration / Q000187:drug effects* / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D015427:Reperfusion Injury / Q000150:complications*; D000098552:Slit Homolog 2 Protein
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D003404:Creatinine; D000098552:Slit Homolog 2 Protein