Regular article
Cardiovascular, pulmonary, and renal pathology
Spleen Tyrosine Kinase Signaling Promotes Myeloid Cell Recruitment and Kidney Damage after Renal Ischemia/Reperfusion Injury

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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.

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Supported by the National Health and Medical Research Council (NHMRC) of Australia grant 1002079 (D.J.N.-P., F.Y.M., J.K.) and a NHMRC Senior Research Fellowship 1058175 (D.J.N.-P.).

F.Y.M. and D.J.N.-P. contributed equally to this work.

Disclosures: K.B. is an employee of and holds stock options in Celgene. D.J.N.-P. has previously received research funding from Celgene for studies unrelated to the present manuscript. CC0417 was supplied by Celgene.

Portions of this work were presented in abstract form at the 49th Annual Meeting of the Australian and New Zealand Society of Nephrology, September 9–11, 2013, Brisbane, QLD, Australia.