title: Aldosterone induces fibrosis, oxidative stress and DNA damage in livers of male rats independent of blood pressure changes.
abstract: Mineralocorticoid receptor blockers show antifibrotic potential in hepatic fibrosis. The mechanism of this protective effect is not known yet, although reactive oxygen species seem to play an important role. Here, we investigated the effects of elevated levels of aldosterone (Ald), the primary ligand of the mineralocorticoid receptor, on livers of rats in a hyperaldosteronism model: aldosterone-induced hypertension. Male Sprague-Dawley rats were treated for 4 weeks with aldosterone. To distinguish if damage caused in the liver depended on increased blood pressure or on increased Ald levels, the mineralocorticoid receptor antagonist spironolactone was given in a subtherapeutic dose, not normalizing blood pressure. To investigate the impact of oxidative stress, the antioxidant tempol was administered. Aldosterone induced fibrosis, detected histopathologically, and by expression analysis of the fibrosis marker, α-smooth muscle actin. Further, the mRNA amount of the profibrotic cytokine TGF-β was increased significantly. Fibrosis could be reduced by scavenging reactive oxygen species, and also by blocking the mineralocorticoid receptor. Furthermore, aldosterone treatment caused oxidative stress and DNA double strand breaks in livers, as well as the elevation of DNA repair activity. An increase of the transcription factor Nrf2, the main regulator of the antioxidative response could be observed, and of its target genes heme oxygenase-1 and γ-glutamylcysteine synthetase. All these effects of aldosterone were prevented by spironolactone and tempol. Already after 4 weeks of treatment, aldosteroneinfusion induced fibrosis in the liver. This effect was independent of elevated blood pressure. DNA damage caused by aldosterone might contribute to fibrosis progression when aldosterone is chronically increased.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Queisser
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Happ
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.
authors.forename: Samuel
authors.initials: S
authors.lastname: Link
authors.affiliation: Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Jahn
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Zimnol
authors.affiliation: Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Geier
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany. Electronic address: schupp@uni-duesseldorf.de.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schupp
mesh_terms: D000818:Animals; D008297:Male; D000450:Aldosterone / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D003497:Cyclic N-Oxides / Q000494:pharmacology; D006651:Histocytochemistry; D008103:Liver Cirrhosis / Q000378:metabolism; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D012313:RNA / Q000737:chemistry / Q000235:genetics; D013113:Spin Labels; D013148:Spironolactone / Q000494:pharmacology; D018709:Statistics, Nonparametric; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism
chemical_list: D000450:Aldosterone; D003497:Cyclic N-Oxides; D000451:Mineralocorticoid Receptor Antagonists; D012313:RNA; D013113:Spin Labels; D013148:Spironolactone; C001803:tempol; D016212:Transforming Growth Factor beta; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat
keywords: DNA damage; Hyperaldosteronism; Mineralocorticoid receptor; Nrf2; α-SMA; γ-H2AX