1. Academic Validation
  2. Neurorescuing effect of Cinacalcet against hypercalcemia-induced nerve injury in chronic kidney disease via TRAF2/cIAP1/KLF2/SERPINA3 signal axis

Neurorescuing effect of Cinacalcet against hypercalcemia-induced nerve injury in chronic kidney disease via TRAF2/cIAP1/KLF2/SERPINA3 signal axis

  • Cell Biol Toxicol. 2022 May 30. doi: 10.1007/s10565-022-09717-1.
Yaochen Cao 1 2 Yingquan Xiong 2 Hongming Sun 3 4 Ziqiang Wang 5
Affiliations

Affiliations

  • 1 The First Affiliated Hospital of Hainan Medical University, Haikou, 571199, People's Republic of China.
  • 2 Department of Nephrology, Charité - Universitätsmedizin Berlin, Campus Mitte, 10117, Berlin, Germany.
  • 3 Department of Neurology, the Fourth Hospital of Daqing, Daqing, 163712, People's Republic of China. [email protected].
  • 4 Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan. [email protected].
  • 5 Department of Nephrology, The First Affiliated Hospital of Hainan Medical University, Haikou, 571199, People's Republic of China.
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.

Keywords

Chronic kidney disease; Cinacalcet; Hypercalcemia; Kruppel-like factor 2; Nerve injury; SERPINA3; TRAF2.

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