SPRED2 controls the severity of cisplatin-induced acute kidney injury by inhibiting ERK activation and TNFα production in mice

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Cisplatin is an effective chemotherapeutic agent used to treat solid tumors, but its clinical use is limited by acute kidney injury (AKI), in which ERK signaling plays a crucial role. Here, we investigated whether Sprouty-related EVH1 domain-containing protein 2 (SPRED2), an endogenous inhibitor of the Ras/Raf/ERK pathway, protects against cisplatin-induced AKI. Spred2 −/− mice showed more severe renal injury and stronger ERK activation than wild-type (WT) mice, whereas pretreatment with the MEK inhibitor U0126 markedly attenuated the injury. In HK-2 cells (proximal tubular cells), SPRED2 knockdown enhanced cisplatin-induced apoptosis and caspase-3 activation, accompanied by decreased Bcl-2 expression. Spred2 −/− kidneys displayed increased macrophage infiltration and elevated Tnfα , Il1b , and Ccl2 expression. Neutralization of TNFα with anti-TNFα antibody ameliorated renal injury and reduced the levels of Il1b and Ccl2 mRNA in Spred2 −/− mice. In vitro, TNFα slightly decreased the viability of control and SPRED2 knockdown HK-2 cells without cisplatin treatment, but the decreased viability was augmented in SPRED2 knockdown cells by cisplatin. Immunohistochemistry revealed that macrophages were the predominant TNFα-positive cell population. Bone marrow–derived macrophages from Spred2 −/− mice produced higher levels of TNFα in response to cisplatin compared with control cells, and this increase was markedly suppressed by U0126. These findings indicate that endogenous SPRED2 protects kidneys from cisplatin-induced AKI by limiting ERK activation, tubular apoptosis, and TNFα-mediated inflammation. • Spred2 -/- mice exhibited more severe renal injury than wild-type (WT) mice with increased ERK activation in response to cisplatin injection. • SPRED2 knockdown in HK-2 cells resulted in decreased cell viability and increased apoptosis. • Spred2 -/- mice showed increased numbers of macrophages and higher levels of Tnfα , Il1b , and Ccl2 mRNA in the kidney, and macrophages appeared the main cell population producing TNFα. • Inhibition of the ERK pathway with U0126 or neutralization of TNFα with anti-TNFα antibody significantly improved cisplatin-induced acute kidney injury.

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