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This study identifies a molecular mechanism of the O-linked N-acetylglucosamine transferase (OGT)-mediated enhancer of zeste homolog 2 (EZH2)\/kr\u00fcppel-like factor 2 (KLF2)\/chemokine (C-X-C motif) ligand 1 (CXCL1) axis underlying the hypercalcemia-induced nerve injury in renal failure. Bioinformatics analyses were used to screen out the key factors in hypercalcemia-induced nerve injury in renal failure. Chronic kidney disease (CKD) was induced by an adenine diet in mice, followed by injection of adenovirus vector carrying short hairpin RNA targeting OGT, followed by behavioral tests and collection of the cerebral cortex for primary neurons. Calcium level in neurons was measured by Fluo-4-am and Perkin Elmer+ Operetta. Neuronal apoptosis and viability were detected by flow cytometry and the MTS method. The binding of EZH2 to KLF2 promoter was verified by chromatin immunoprecipitation assay. The concentration of Ca<jats:sup>2+<\/jats:sup> in brain tissues of CKD model mice was increased, and nerve functions were obviously damaged. High expression of OGT occurred in kidney tissue of CKD model mice. Silencing OGT reduced the hypercalcemia-induced toxicity of neurons by inhibiting the expression of EZH2, which elevated the expression of CXCL1 in primary neurons by diminishing KLF2. Silencing OGT attenuated hypercalcemia-induced neurotoxicity by regulating the EZH2\/KLF2\/CXCL1 axis. In vivo experiments further confirmed that silencing OGT could reduce hypercalcemia-induced nerve injury in CKD mice. Taken together, silencing OGT downregulates EZH2, which increases the expression of KLF2 and then decreases the expression of CXCL1, thus alleviating hypercalcemia-induced nerve injury in renal failure.<\/jats:p>","DOI":"10.1038\/s41419-021-04022-x","type":"journal-article","created":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T11:02:58Z","timestamp":1630321378000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Silencing of O-linked N-acetylglucosamine transferase ameliorates hypercalcemia-induced neurotoxicity in renal failure by regulating EZH2\/KLF2\/CXCL1 axis"],"prefix":"10.1038","volume":"12","author":[{"given":"Yaochen","family":"Cao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1302-5293","authenticated-orcid":false,"given":"Hongming","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,30]]},"reference":[{"key":"4022_CR1","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1055\/s-0031-1277984","volume":"31","author":"JL Seifter","year":"2011","unstructured":"Seifter JL, Samuels MA. 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All experimental procedures obeyed the Guidelines for the Care and Use of Laboratory Animals issued by the National Institutes of Health.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics statement"}},{"value":"The authors declare no competing interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"819"}}