Jin Xiucai, Rong Shu, Yuan Weijie, Gu Lijie, Jia Jieshuang, Wang Ling, Yu Honglei, Zhuge Yifeng
Department of Ultrasound, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China.
Department of Nephrology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Physiol. 2018 Jun 5;9:665. doi: 10.3389/fphys.2018.00665. eCollection 2018.
Vascular calcification (VC) is common in chronic kidney disease (CKD), where cardiovascular mortality remains the leading cause of death. Here, we examined the role of high-mobility group box1 (HMGB1), a nuclear DNA-binding protein involved in inflammation, in aortic calcification and renal dysfunction induced by high phosphate in a mouse model of CKD induced by 5/6 nephrectomy. HMGB1 and kidney function markers were measured by ELISA in the serum of CKD patients and in CKD mice. Sections of the aortas of mice were analyzed by immunofluorescence and Alizarin red staining, and protein lysates were generated to analyze the expression of related proteins in response to silencing of HMGB1 or β-catenin by western blotting. Our results showed that serum HMGB1 levels were significantly higher in CKD patients than in healthy controls and related to disease stage. High phosphate promoted the translocation of HMGB1 from the nucleus to the cytosol and aortic calcification in CKD mice , whereas HMGB1 knockdown ameliorated part of renal and vascular function. β-catenin silencing reversed high phosphate-induced calcification and restored renal marker levels. Taken together, our results suggest that HMGB1 is involved in VC associated with CKD via a mechanism involving the β-catenin.
血管钙化（VC）在慢性肾脏病（CKD）中很常见，在CKD中，心血管疾病死亡率仍然是主要死因。在此，我们在5/6肾切除诱导的CKD小鼠模型中，研究了参与炎症反应的核DNA结合蛋白高迁移率族蛋白B1（HMGB1）在高磷诱导的主动脉钙化和肾功能障碍中的作用。通过酶联免疫吸附测定（ELISA）检测CKD患者和CKD小鼠血清中的HMGB1和肾功能标志物。通过免疫荧光和茜素红染色分析小鼠主动脉切片，并制备蛋白质裂解物，通过蛋白质印迹法分析沉默HMGB1或β-连环蛋白后相关蛋白的表达。我们的结果表明，CKD患者血清HMGB1水平显著高于健康对照，且与疾病分期相关。高磷促进CKD小鼠中HMGB1从细胞核向细胞质的转位以及主动脉钙化，而敲低HMGB1可改善部分肾脏和血管功能。沉默β-连环蛋白可逆转高磷诱导的钙化并恢复肾脏标志物水平。综上所述，我们的结果表明，HMGB1通过涉及β-连环蛋白的机制参与与CKD相关的VC。
