Spleen Tyrosine Kinase Signaling Promotes Myeloid Cell Recruitment and Kidney Damage after Renal Ischemia/Reperfusion Injury

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 myeloidcell adhesion to activated endothelial cells in vitro ; however, whether Sykis required for myeloidcell recruitment and tubular damage in I/R injury is unknown. Therefore, we investigated the function of Sykin mouse I/R injury using two different approaches. C57Bl/6J mice underwent bilateral warm ischemiaand were sacrificed after 30 minutes or 24 hours of reperfusion. Mice were treated with the Sykinhibitor CC0417, or vehicle, beginning 1 hour before surgery. Sykwas 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 Sykgene deletion in myeloidcells ( 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 Syksignaling in renal I/R injury and identify Sykas a potential therapeutic target in this condition.