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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The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Yaochen Cao and Yingquan Xiong conceived and designed research. Hongming Sun performed experiments. Yaochen Cao interpreted results of experiments. Hongming Sun analyzed data and prepared Figures. Yingquan Xiong drafted paper. Yaochen Cao and Hongming Sun edited and revised manuscript. Ziqiang Wang contributed to the revision. All authors read and approved final version of manuscript.
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Animal experiments were approved by the Animal Care and Use Committee of the Fourth Hospital of Daqing and performed in accordance with Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health.
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Yaochen Cao is sponsored by China Scholarship Council.
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10565_2022_9717_Fig8_ESM.png
Supplementary Fig. 1 Effect of TRAF2 and cIAP1 on the KLF2 ubiquitination. A: KLF2 ubiquitination in TCMK-1 cells treated with oe-TRAF2 or combined with sh-cIAP1 determined by Co-IP and Western blot; B: KLF2 ubiquitination in TCMK-1 cells treated with sh-TRAF2 or combined with oe-cIAP1 determined by Co-IP and Western blot. All cell experiments were repeated 3 times independently. (PNG 444 KB)
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Cao, Y., Xiong, Y., Sun, H. et al. Neurorescuing effect of Cinacalcet against hypercalcemia-induced nerve injury in chronic kidney disease via TRAF2/cIAP1/KLF2/SERPINA3 signal axis. Cell Biol Toxicol 39, 1–17 (2023). https://doi.org/10.1007/s10565-022-09717-1
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DOI: https://doi.org/10.1007/s10565-022-09717-1