title: CXCL12 protects pancreatic β-cells from oxidative stress by a Nrf2-induced increase in catalase expression and activity.
abstract: Due to intrinsically low levels of antioxidant enzyme expression and activity, insulin producing pancreatic β-cells are particularly susceptible to free radical attack. In diabetes mellitus, which is accompanied by high levels of oxidative stress, this feature of β-cells significantly contributes to their damage and dysfunction. In light of the documented pro-survival effect of chemokine C-X-C Ligand 12 (CXCL12) on pancreatic β-cells, we examined its potential role in antioxidant protection. We report that CXCL12 overexpression enhanced the resistance of rat insulinoma (Rin-5F) and primary pancreatic islet cells to hydrogen peroxide (H2O2). CXCL12 lowered the levels of DNA damage and lipid peroxidation and preserved insulin expression. This effect was mediated through an increase in catalase (CAT) activity. By activating downstream p38, Akt and ERK kinases, CXCL12 facilitated Nrf2 nuclear translocation and enhanced its binding to the CAT gene promoter, inducing constitutive CAT expression and activity that was essential for protecting β-cells from H2O2.
authors.affiliation: Department of Molecular Biology, Institute for Biological Research, University of Belgrade.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Dinić
authors.forename: Nevena
authors.initials: N
authors.lastname: Grdović
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Uskoković
authors.forename: Miloš
authors.initials: M
authors.lastname: Đorđević
authors.forename: Mirjana
authors.initials: M
authors.lastname: Mihailović
authors.forename: Jelena Arambašić
authors.initials: JA
authors.lastname: Jovanović
authors.forename: Goran
authors.initials: G
authors.lastname: Poznanović
authors.forename: Melita
authors.initials: M
authors.lastname: Vidaković
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001483:Base Sequence; D002374:Catalase / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D017208:Rats, Wistar; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000975:Antioxidants; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D014157:Transcription Factors; D006861:Hydrogen Peroxide; D002374:Catalase