Wang Feng, Yin Jianyong, Lin Yingying, Zhang Fangfei, Liu Xuanchen, Zhang Guangyuan, Kong Yiwei, Lu Zeyuan, Wu Rui, Wang Niansong, Xing Tao, Qian Youcun
Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China; State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China.
Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Kidney Int. 2020 Jun;97(6):1219-1229. doi: 10.1016/j.kint.2020.01.015. Epub 2020 Feb 4.
Cytokines are necessary to trigger the inflammatory response in kidney ischemia/reperfusion injury. Interleukin-17C (IL-17C), a unique member of the IL-17 family, is a cytokine produced by epithelial cells implicated in host defense and autoimmune diseases. However, little is known about the role of IL-17C in acute kidney injury. We investigated this and found that IL-17C was significantly increased in kidney biopsies of patients and mice with acute kidney injury. Exposure to hypoxia induced upregulation of IL-17C in kidney tubular epithelial cells. To further investigate the role of IL-17C, kidney ischemia/reperfusion injury was induced in mice. Inhibition of IL-17C action with a neutralizing antibody or IL-17 receptor E (IL-17RE) knockout attenuated tubular injury, kidney oxidative stress, and kidney inflammation. Mechanistically, both IL-17C neutralization and IL-17RE knockout attenuated TH17 activation and IL-17A expression in kidneys of mice with acute kidney injury. TNF-α and IL-1β, downstream cytokines of IL-17C, were also reduced in IL-17C antibody pretreated and IL-17RE knockout mice. Additionally, IL-17C knockdown with siRNA decreased hypoxia-induced inflammation in kidney tubular cells and silencing IL-17RE abrogated the effects of IL-17C in kidney tubular cells. Thus, IL-17C may participate in the inflammatory response of acute kidney injury and inhibition of IL-17C or blockade of IL-17 RE may be a novel therapeutic strategy for the treatment of acute kidney injury.
细胞因子是引发肾脏缺血/再灌注损伤炎症反应所必需的。白细胞介素-17C（IL-17C）是IL-17家族的独特成员，是一种由上皮细胞产生的细胞因子，与宿主防御和自身免疫性疾病有关。然而，关于IL-17C在急性肾损伤中的作用知之甚少。我们对此进行了研究，发现急性肾损伤患者和小鼠的肾活检组织中IL-17C显著增加。暴露于缺氧环境会诱导肾小管上皮细胞中IL-17C的上调。为了进一步研究IL-17C的作用，我们在小鼠中诱导了肾脏缺血/再灌注损伤。用中和抗体抑制IL-17C的作用或敲除IL-17受体E（IL-17RE）可减轻肾小管损伤、肾脏氧化应激和肾脏炎症。从机制上讲，IL-17C中和和IL-17RE敲除均减弱了急性肾损伤小鼠肾脏中TH17的激活和IL-17A的表达。IL-17C的下游细胞因子TNF-α和IL-1β在IL-17C抗体预处理小鼠和IL-17RE敲除小鼠中也有所减少。此外，用小干扰RNA（siRNA）敲低IL-17C可降低缺氧诱导的肾小管细胞炎症，而沉默IL-17RE可消除IL-17C在肾小管细胞中的作用。因此，IL-17C可能参与急性肾损伤的炎症反应，抑制IL-17C或阻断IL-17RE可能是治疗急性肾损伤的一种新的治疗策略。
