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Title: | Spleen Tyrosine Kinase Signaling Promotes Myeloid Cell Recruitment and Kidney Damage after Renal Ischemia/Reperfusion Injury. | Authors: | Nikolic-Paterson D.J. ;Ma F.Y.;Kanellis J.;Blease K.;Ryan J. | Institution: | (Ryan, Kanellis, Ma, Nikolic-Paterson) Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia (Ryan, Kanellis, Ma, Nikolic-Paterson) Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia (Blease) Department of Pharmacology, Celgene, San Diego, California, United States | Issue Date: | 17-Oct-2016 | Copyright year: | 2016 | Publisher: | Elsevier Inc. (E-mail: usjcs@elsevier.com) | Place of publication: | United States | Publication information: | American Journal of Pathology. 186 (8) (pp 2032-2042), 2016. Date of Publication: 01 Aug 2016. | Journal: | American Journal of Pathology | Abstract: | Ischemia/reperfusion (I/R) injury is an important cause of acute and chronic renal failure. Neutrophils and macrophages, by integrin-based recruitment, play a key role in renal I/R injury. Integrin-based activation of spleen tyrosine kinase (Syk) contributes to myeloid cell adhesion to activated endothelial cells in vitro; however, whether Syk is required for myeloid cell recruitment and tubular damage in I/R injury is unknown. Therefore, we investigated the function of Syk in mouse I/R injury using two different approaches. C57Bl/6J mice underwent bilateral warm ischemia and were sacrificed after 30 minutes or 24 hours of reperfusion. Mice were treated with the Syk inhibitor CC0417, or vehicle, beginning 1 hour before surgery. Syk was expressed by infiltrating neutrophils, macrophages, and platelets in vehicle-treated I/R injury which exhibited severe renal failure and tubular damage at 24 hours. CC0417 treatment markedly reduced neutrophil, macrophage, and platelet accumulation with improved renal function and reduced tubular damage. Next, we compared mice with conditional Syk gene deletion in myeloid cells (SykMy) versus Sykf/f littermate controls in a 24-hour study. SykMy mice also showed a marked reduction in neutrophil and macrophage infiltration with significant protection from I/R-induced acute renal failure and tubular damage. These studies define a pathologic role for myeloid Syk signaling in renal I/R injury and identify Syk as a potential therapeutic target in this condition.Copyright © 2016 American Society for Investigative Pathology | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1016/j.ajpath.2016.04.007 | PubMed URL: | 27322771 [http://www.ncbi.nlm.nih.gov/pubmed/?term=27322771] | ISSN: | 0002-9440 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/39832 | Type: | Article | Subjects: | interleukin 6/ec [Endogenous Compound] nitrogen/ec [Endogenous Compound] animal cell animal experiment animal model article *bone marrow cell C57BL 6 mouse cell infiltration controlled study creatinine blood level disease severity gene deletion histology immunohistochemistry kidney function *kidney injury/dt [Drug Therapy] *kidney injury/et [Etiology] *kidney injury/pc [Prevention] kidney injury/dt [Drug Therapy] *kidney ischemia/dt [Drug Therapy] *kidney ischemia/et [Etiology] *kidney ischemia/pc [Prevention] kidney ischemia/dt [Drug Therapy] kidney tubule disorder/et [Etiology] kidney tubule necrosis/dt [Drug Therapy] kidney tubule necrosis/et [Etiology] macrophage male mouse neutrophil chemotaxis nonhuman priority journal real time polymerase chain reaction renal protection *reperfusion injury/dt [Drug Therapy] *reperfusion injury/et [Etiology] *reperfusion injury/pc [Prevention] reperfusion injury/dt [Drug Therapy] reverse transcription polymerase chain reaction kidney injury molecule 1/ec [Endogenous Compound] protective agent/dv [Drug Development] protective agent/dt [Drug Therapy] protective agent/po [Oral Drug Administration] protective agent/pd [Pharmacology] *protein kinase Syk/ec [Endogenous Compound] protein kinase Syk inhibitor/dv [Drug Development] protein kinase Syk inhibitor/dt [Drug Therapy] protein kinase Syk inhibitor/po [Oral Drug Administration] protein kinase Syk inhibitor/pd [Pharmacology] tumor necrosis factor/ec [Endogenous Compound] unclassified drug urea/ec [Endogenous Compound] cc 0417/dv [Drug Development] cc 0417/dt [Drug Therapy] cc 0417/po [Oral Drug Administration] cc 0417/pd [Pharmacology] animal tissue severe renal impairment/et [Etiology] *signal transduction thrombocyte activation thrombocyte aggregation macrophage elastase/ec [Endogenous Compound] messenger RNA/ec [Endogenous Compound] monocyte chemotactic protein 1/ec [Endogenous Compound] upregulation urea nitrogen blood level CD68 antigen/ec [Endogenous Compound] creatinine/ec [Endogenous Compound] cryopyrin/ec [Endogenous Compound] gelatinase B/ec [Endogenous Compound] heme oxygenase 1/ec [Endogenous Compound] inducible nitric oxide synthase/ec [Endogenous Compound] interleukin 18/ec [Endogenous Compound] interleukin 1beta/ec [Endogenous Compound] immunohistochemistry kidney function *kidney injury / *drug therapy / *etiology / *prevention kidney injury / drug therapy *kidney ischemia / *drug therapy / *etiology / *prevention kidney ischemia / drug therapy kidney tubule disorder / etiology kidney tubule necrosis / drug therapy / etiology macrophage male mouse neutrophil chemotaxis nonhuman priority journal real time polymerase chain reaction renal protection *reperfusion injury / *drug therapy / *etiology / *prevention reperfusion injury / drug therapy reverse transcription polymerase chain reaction severe renal impairment / etiology *signal transduction thrombocyte activation thrombocyte aggregation Article urea nitrogen blood level animal tissue animal model animal experiment animal cell upregulation *bone marrow cell C57BL 6 mouse cell infiltration controlled study creatinine blood level disease severity gene deletion histology |
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