title: Aldosterone activates the oncogenic signals ERK1/2 and STAT3 via redox-regulated mechanisms.
abstract: Epidemiological studies found an increased risk for kidney cancer in hypertensive patients, of which a subgroup has high aldosterone (Ald) levels. We recently showed that Ald is genotoxic both in kidney tubular cells and in rats with mineralocorticoid-mediated hypertension. The present work investigated in vitro and in vivo, if the oxidative stress-mediated activation of the ERK1/2 pathway, and its downstream target STAT3, could be one mechanism involved in the potential oncogenic capability of excess Ald exposure. The effects of excess Ald were investigated in LLC-PK1 cells and in Ald-induced hypertensive rats. Ald caused cRaf, MEK1/2, and ERK1/2 phosphorylation both in LLC-PK1 cells and in rat kidneys. ERK1/2 activation led to an increased phosphorylation of MSK1, p90RSK, and STAT3. The involvement of ERK1/2 in the activation of STAT3 was evidenced by the capacity of the MEK inhibitor U0126 to prevent Ald-mediated ERK1/2 and STAT3 phosphorylation. Both in vitro and in vivo, the activation of ERK1/2 and STAT3 by Ald was dependent on the mineralocorticoid receptor and was triggered by an increase in cellular oxidants. Ald-mediated oxidant increase was in part due to the activation of the enzymes NADPH oxidase and NO synthase. Proliferation was significantly enhanced and apoptosis decreased in Ald-treated rat kidneys and/or LLC-PK1 cells. Results support the concept that the oxidant-mediated long-term activation of ERK1/2/STAT3 by persistently high Ald levels could trigger proliferative and prosurvival events. Ald-mediated promotion of cell survival and DNA damage could result in kidney cell transformation and initiation of cancer in hypertensive patients with hyperaldosteronism.
authors.affiliation: Institute of Toxicology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.|Department of Nutrition, University of California, Davis, California.
authors.forename: Nina
authors.initials: N
authors.lastname: Queisser
authors.affiliation: Institute of Toxicology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schupp
authors.affiliation: Institute of Toxicology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Schwarz
authors.affiliation: Institute of Toxicology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Hartmann
authors.affiliation: Department of Nutrition, University of California, Davis, California.
authors.forename: Gerardo G
authors.initials: GG
authors.lastname: Mackenzie
authors.affiliation: Department of Nutrition, University of California, Davis, California.|Department of Environmental Toxicology, University of California, Davis, California.
authors.forename: Patricia I
authors.identifier: 0000-0001-7462-1641
authors.initials: PI
authors.lastname: Oteiza
mesh_terms: D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004789:Enzyme Activation; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: D050796:STAT3 Transcription Factor; D000450:Aldosterone; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: ERK1/2; STAT3; aldosterone; kidney cancer; oxidative stress