title: Hydroxytyrosol decreases the oxidative and nitrosative stress levels and promotes angiogenesis through HIF-1 independent mechanisms in renal hypoxic cells.
abstract: In the kidney, tissue oxygen tension is comparatively low and this renders this organ more prone to hypoxic injury. In fact, hypoxia has a central role in the development and progression of renal disease. The recovery from this situation is dependent on the degree to which sublethally damaged cells restore normal function. The master regulator of the hypoxic response is hypoxia-inducible factor-1 (HIF-1). HIF-1 activity depends on the HIF-1α subunit level which is regulated by oxygen, nitric oxide (NO), reactive oxygen species and mTOR. Given the antioxidant and antinitrosative properties ascribed to hydroxytyrosol (HT), this study evaluates the impact of this olive oil polyphenol on the response to hypoxia in kidney cells. For this purpose, the human embryonic kidney HEK293T cell line was treated with HT and cultured under sublethal hypoxic conditions. Our results demonstrate that HT treatment decreases both, post-hypoxic reactive oxygen species and NO levels and, consequently, HIF-1α accumulation. However, HT does not affect mTOR activation or the factor inhibiting HIF level but promotes the expression of angiogenic proteins, suggesting that HT activates an adaptive response to hypoxia in a HIF-1α-independent pathway. In fact, this effect could be ascribed to the up-regulation of estrogen-related receptor α. In conclusion, our results suggest that in renal hypoxia, HT treatment might act as an effective preventive therapeutic approach to decrease stress and to improve the adaptive response to this pathological situation.
authors.affiliation: Department of Experimental Biology, University of Jaén, Paraje Las Lagunillas s/n, 23071-Jaén, Spain. esiles@ujaen.es.
authors.forename: Esther
authors.initials: E
authors.lastname: Martínez-Lara
authors.affiliation: Department of Experimental Biology, University of Jaén, Paraje Las Lagunillas s/n, 23071-Jaén, Spain. esiles@ujaen.es.
authors.forename: Ana
authors.initials: A
authors.lastname: Peña
authors.affiliation: Department of Experimental Biology, University of Jaén, Paraje Las Lagunillas s/n, 23071-Jaén, Spain. esiles@ujaen.es.
authors.forename: Jesús
authors.initials: J
authors.lastname: Calahorra
authors.affiliation: Department of Experimental Biology, University of Jaén, Paraje Las Lagunillas s/n, 23071-Jaén, Spain. esiles@ujaen.es.
authors.forename: Ana
authors.initials: A
authors.lastname: Cañuelo
authors.affiliation: Department of Experimental Biology, University of Jaén, Paraje Las Lagunillas s/n, 23071-Jaén, Spain. esiles@ujaen.es.
authors.forename: Eva
authors.initials: E
authors.lastname: Siles
mesh_terms: D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D000069463:Olive Oil / Q000737:chemistry; D018384:Oxidative Stress / Q000187:drug effects*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D051793:Hypoxia-Inducible Factor 1; D000069463:Olive Oil; C005975:3,4-dihydroxyphenylethanol; D006861:Hydrogen Peroxide; D010626:Phenylethyl Alcohol