Abstract
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.
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