title: Aldosterone activates transcription factor Nrf2 in kidney cells both in vitro and in vivo.
abstract: OBJECTIVE
  An increased kidney cancer risk was found in hypertensive patients, who frequently exhibit hyperaldosteronism, known to contribute to kidney injury, with oxidative stress playing an important role. The capacity of kidney cells to up-regulate transcription factor nuclear factor-erythroid-2-related factor 2 (Nrf2), a key regulator of the cellular antioxidative defense, as a prevention of aldosterone-induced oxidative damage was investigated both in vitro and in vivo.
  
  
  RESULTS
  Aldosterone activated Nrf2 and increased the expression of enzymes involved in glutathione (GSH) synthesis and detoxification. This activation depended on the mineralocorticoid receptor (MR) and oxidative stress. In vitro, Nrf2 activation, GSH amounts, and target gene levels decreased after 24 h, while oxidant levels remained high. Nrf2 activation could not protect cells against oxidative DNA damage, as aldosterone-induced double-strand breaks and 7,8-dihydro-8-oxo-guanine (8-oxodG) lesions steadily rose. The Nrf2 activator sulforaphane enhanced the Nrf2 response both in vitro and in vivo, thereby preventing aldosterone-induced DNA damage. In vivo, Nrf2 activation further had beneficial effects on the aldosterone-caused blood pressure increase and loss of kidney function.
  
  
  METHODS
  This is the first study showing the activation of Nrf2 by aldosterone. Moreover, the results identify sulforaphane as a substance that is capable of preventing aldosterone-induced damage both in vivo and in vitro.
  
  
  CONCLUSIONS
  Aldosterone-induced Nrf2 adaptive response cannot neutralize oxidative actions of chronically increased aldosterone, which, therefore could be causally involved in the increased cancer incidence of hypertensive individuals. Enhancing the cellular antioxidative defense with sulforaphane might exhibit beneficial effects.
authors: 1 Department of Toxicology, University of Würzburg , Würzburg, Bavaria, Germany .
authors: Nina
authors: N
authors: Queisser
authors: Patricia I
authors: PI
authors: Oteiza
authors: Samuel
authors: S
authors: Link
authors: Valentin
authors: V
authors: Hey
authors: Helga
authors: H
authors: Stopper
authors: Nicole
authors: N
authors: Schupp
mesh_terms: D000450:Aldosterone / Q000502:physiology*; D000818:Animals; D004249:DNA Damage; D015870:Gene Expression; D005978:Glutathione / Q000096:biosynthesis; D017879:Isothiocyanates / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000166:cytology; D018374:LLC-PK1 Cells; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D015398:Signal Transduction; D013454:Sulfoxides; D013552:Swine; D015533:Transcriptional Activation
chemical_list: D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D018161:Receptors, Mineralocorticoid; D013454:Sulfoxides; D000450:Aldosterone; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; C016766:sulforaphane; D005978:Glutathione