Hypercalcemia is a common complication in chronic kidney disease (CKD) and unfortunately contributes to nerve injury. This study aims to investigate the potential role and underlying mechanisms of Cinacalcet (CIN) in hypercalcemia-driven nerve injury in CKD. A CKD mouse model was first established by adenine feeding to identify the therapeutic effects of CIN. Molecules related to CIN and CKD were predicted by bioinformatics analysis and their expression in the kidney tissues of CKD mice was measured by immunochemistry. Gain- and loss-of-functions assays were performed both in vitro and in vivo to evaluate their effects on nerve injury in CKD, as reflected by Scr and BUN, and brain calcium content as well as behavior tests. CIN ameliorated hypercalcemia-driven nerve injury in CKD mice. Interactions among TRAF2, an E3-ubiquitin ligase, KLF2, and SERPINA3 were bioinformatically predicted on CIN effect. CIN restricted the ubiquitin-mediated degradation of KLF2 by downregulating TRAF2. KLF2 targeted and inversely regulated SERPINA3 to repress hypercalcemia-driven nerve injury in CKD. CIN was substantiated in vivo to ameliorate hypercalcemia-driven nerve injury in CKD mice through the TRAF2/KLF2/SERPINA3 regulatory axis. Together, CIN suppresses SERPINA3 expression via TRAF2-mediated inhibition of the ubiquitin-dependent degradation of KLF2, thus repressing hypercalcemia-induced nerve injury in CKD mice.

Graphical abstract

中文翻译：

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西那卡塞通过 TRAF2/cIAP1/KLF2/SERPINA3 信号轴对慢性肾脏病高钙血症所致神经损伤的神经拯救作用

高钙血症是慢性肾脏病 (CKD) 的常见并发症，不幸的是会导致神经损伤。本研究旨在探讨西那卡塞（CIN）在 CKD 中高钙血症驱动的神经损伤中的潜在作用和潜在机制。首先通过腺嘌呤喂养建立 CKD 小鼠模型，以鉴定 CIN 的治疗效果。通过生物信息学分析预测与CIN和CKD相关的分子，并通过免疫化学测定其在CKD小鼠肾组织中的表达。在体外和体内进行功能获得和丧失测定，以评估它们对 CKD 神经损伤的影响，如 Scr 和 BUN、脑钙含量以及行为测试所反映的。CIN 改善 CKD 小鼠高钙血症引起的神经损伤。通过生物信息学方法预测了 TRAF2、E3 泛素连接酶、KLF2 和 SERPINA3 之间的相互作用对 CIN 的影响。CIN 通过下调 TRAF2 来限制泛素介导的 KLF2 降解。KLF2 靶向并反向调节 SERPINA3 以抑制 CKD 中高钙血症驱动的神经损伤。体内证实 CIN 可通过 TRAF2/KLF2/SERPINA3 调节轴改善 CKD 小鼠高钙血症引起的神经损伤。CIN 通过 TRAF2 介导的 KLF2 泛素依赖性降解抑制来抑制 SERPINA3 表达，从而抑制 CKD 小鼠中高钙血症引起的神经损伤。

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