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

// Chongxiang Xiong 1, 2, * , Xiujuan Zang 3, * , Xiaoxu Zhou 2 , Lirong Liu 2 , Monica V. Masucci 2 , Jinhua Tang 1 , Xuezhu Li 1 , Na Liu 1 , George Bayliss 2 , Ting C. Zhao 4 , Shougang Zhuang 1, 2 1 Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China 2 Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI 02903, USA 3 Department of Nephrology, Shanghai Songjiang District Central Hospital, Shanghai, China 4 Department of Surgery, Boston University Medical School, Roger Williams Medical Center, Boston University, Providence, RI, 02908, USA * These authors contributed equally to this work Correspondence to: Shougang Zhuang, email: szhuang@lifespan.org Keywords: Src kinase, acute kidney injury, ischemia/reperfusion, E-cadherin, metalloproteinase Received: January 10, 2017      Accepted: March 02, 2017      Published: March 10, 2017 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.