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.
Highlights
Acute kidney injury (AKI) is a critical clinical syndrome caused by a variety of insults, including ischemia/reperfusion (I/R) [1, 2]
As a first step towards understanding the role of Src in the kidney after IR injury, we examined the effect of PP1 on the phosphorylation of Src at tyrosine 416, Immunoblot analysis revealed that phosphorylated Src at Tyr416 (p-Src) was not detectable in the sham-operated kidney, but its level was dramatically increased at 48 h after ischemia/ reperfusion (I/R) injury (Figure 1A, 1B)
As the phosphorylation at tyrosine 416 positively regulates the activation of Src kinase [28], our data suggest that injury to the kidney induces Src activation in renal tubular cells and that PP1 is a potent inhibitor of Src
Summary
Acute kidney injury (AKI) is a critical clinical syndrome caused by a variety of insults, including ischemia/reperfusion (I/R) [1, 2]. The molecular mechanisms of AKI remain only partially understood, and there are no therapeutic options to alter natural history. Renal tubular injury and death are caused by multiple mechanisms, loss of integrity of renal parenchyma plays an essential role [7]. I/R injury can trigger an altered distribution and/or degradation of tight and adherens junction proteins resulting in loss of barrier function, thereby leading to backleak and renal dysfunction [8].
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