title: Aldosterone induces oxidative stress, oxidative DNA damage and NF-κB-activation in kidney tubule cells.
abstract: An increase of the mineralocorticoid aldosterone is induced by a stimulated renin-angiotensin system in a subgroup of hypertensive patients. Epidemiological studies find higher cancer mortality in hypertensive patients and an increased risk to develop kidney cancer. This work investigated the involvement of oxidants in the genotoxicity of aldosterone and on a potential activation of transcription factor nuclear factor-κB (NF-κB) in kidney tubule cells. Aldosterone, at concentrations as low as 1 nM caused a significant increase of DNA damage, as assessed by comet assay and micronucleus frequency test. Aldosterone also led to a dose-dependent activation of NF-κB. Time courses of DNA damage and NF-κB-activation showed that these effects already occurred after 5 and 3 min of aldosterone exposure, respectively, suggesting non-genomic events of the hormone. Antioxidants prevented aldosterone-induced DNA damage and NF-κB-activation, indicating the involvement of oxidants. In fact, aldosterone caused an increase in intracellular oxidant levels, and in particular of superoxide anions. As a consequence, increased levels of the oxidized DNA modification 7,8-dihydro-8-oxo-guanine were observed in aldosterone-treated kidney cells. Aldosterone-induced DNA damage and NF-κB-activation was dependent on the involvement of the mineralocorticoid receptor. The induction of oxidant-mediated genotoxic effects, and of a long-term activation of the potentially oncogenic cell signal NF-κB by aldosterone could contribute to the increased kidney cancer incidence in hypertensive patients.
authors.affiliation: Department of Toxicology, University of Würzburg, Würzburg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Queisser
authors.forename: Patricia I
authors.initials: PI
authors.lastname: Oteiza
authors.forename: Helga
authors.initials: H
authors.lastname: Stopper
authors.forename: Rajaraman G
authors.initials: RG
authors.lastname: Oli
authors.forename: Nicole
authors.initials: N
authors.lastname: Schupp
mesh_terms: D000450:Aldosterone / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D004249:DNA Damage; D004285:Dogs; D006147:Guanine / Q000031:analogs & derivatives / Q000032:analysis; D007680:Kidney Neoplasms / Q000378:metabolism*; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D013481:Superoxides / Q000032:analysis; D013552:Swine
chemical_list: C453560:7,8-dihydro-8-oxoguanine; D000975:Antioxidants; D016328:NF-kappa B; D018161:Receptors, Mineralocorticoid; D013481:Superoxides; D000450:Aldosterone; D006147:Guanine