Pharmacological inhibition of Src kinase protects against acute kidney injury in a murine model of renal ischemia/reperfusion

Abstract

Activation of Src kinase has been implicated in the pathogenesis of acute brain, liver, and lung injury. However, the role of Src in acute kidney injury (AKI) remains unestablished. To address this, we evaluated the effects of Src inhibition on renal dysfunction and pathological changes in a murine model of AKI induced by ischemia/reperfusion (I/R). I/R injury to the kidney resulted in increased Src phosphorylation at tyrosine 416 (activation). Administration of PP1, a highly selective Src inhibitor, blocked Src phosphorylation, improved renal function and ameliorated renal pathological damage. PP1 treatment also suppressed renal expression of neutrophil gelatinase-associated lipocalin and reduced apoptosis in the injured kidney. Moreover, Src inhibition prevented downregulation of several adherens and tight junction proteins, including E-cadherin, ZO-1, and claudins-1/-4 in the kidney after I/R injury as well as in cultured renal proximal tubular cells following oxidative stress. Finally, PP1 inhibited I/R–induced renal expression of matrix metalloproteinase-2 and -9, phosphorylation of extracellular signal–regulated kinases1/2, signal transducer and activator of transcription-3, and nuclear factor-κB, and the infiltration of macrophages into the kidney. These data indicate that Src is a pivotal mediator of renal epithelial injury and that its inhibition may have a therapeutic potential to treat AKI.