title: Vitamin A (retinol) up-regulates the receptor for advanced glycation endproducts (RAGE) through p38 and Akt oxidant-dependent activation.
abstract: Retinol (vitamin A) is believed to exert preventive/protective effects against malignant, neurodegenerative and cardiovascular diseases by acting as an antioxidant. However, later clinical and experimental data show a pro-oxidant action of retinol and other retinoids at specific conditions. The receptor for advanced glycation endproducts (RAGE) is a pattern recognition receptor, being activated by different ligands such as S100 proteins, HMGB1 (amphoterin), β-amyloid peptide and advanced glycation endproducts (AGE). RAGE activation influences a wide range of pathological conditions such as diabetes, pro-inflammatory states and neurodegenerative processes. Here, we investigated the involvement of different mitogen-activated protein kinases (MAPK: ERK1/2, p38 and JNK), PKC, PKA and Akt in the up-regulation of RAGE by retinol. As previously reported, we observed that the increase in RAGE immunocontent by retinol is reversed by antioxidant co-treatment, indicating the involvement of oxidative stress in this process. Furthermore, the p38 inhibitor SB203580 and the Akt inhibitor LY294002 also decreased the effect of retinol on RAGE levels, suggesting the involvement of these protein kinases in such effect. Both p38 and Akt phosphorylation were increased by treatment with pro-oxidant concentrations of retinol, and the antioxidant co-treatment blocked this effect, indicating that activation of p38 and Akt during retinol treatment is dependent on reactive species production. The 2',7'-dichlorohydrofluorescein diacetate (DCFH) assay also indicated that retinol treatment enhances cellular reactive species production. Altogether, these data indicate that RAGE up-regulation by retinol is mediated by the free radical-dependent activation of p38 and Akt.
authors.affiliation: Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. dgelain@yahoo.com.br
authors.forename: Daniel Pens
authors.initials: DP
authors.lastname: Gelain
authors.forename: Matheus Augusto
authors.initials: MA
authors.lastname: de Bittencourt Pasquali
authors.forename: Fernanda Freitas
authors.initials: FF
authors.lastname: Caregnato
authors.forename: José Claudio Fonseca
authors.initials: JC
authors.lastname: Moreira
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D012708:Sertoli Cells / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014801:Vitamin A / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D002867:Chromones; D016166:Free Radical Scavengers; D007093:Imidazoles; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014801:Vitamin A; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580