title: Blood pressure has only minor influence on aldosterone-induced oxidative stress and DNA damage in vivo.
abstract: Epidemiological studies found an increased kidney cancer risk in hypertensive patients. These patients frequently present an increase in the mineralocorticoid aldosterone (Ald) due to a stimulated renin angiotensin aldosterone system (RAAS). Recently, we showed pro-oxidative and genotoxic effects of Ald in vitro. Here, we investigated the influence of blood pressure on aldosterone-induced oxidative damage. To distinguish whether effects in Sprague-Dawley rats treated with Ald were caused by Ald or by increased blood pressure, the mineralocorticoid receptor (MR) antagonist spironolactone was administered in a subtherapeutical dose, not lowering the blood pressure, and hydralazine, a RAAS-independent vasodilator, was given to normalize the pressure. With the antioxidant tempol, oxidative stress-dependent effects were demonstrated. Ald treatment caused kidney damage and oxidative and nitrative stress. Structural DNA damage and the mutagenic oxidative base modification 7,8-dihydro-8-oxoguanine were increased, as well as DNA repair activity and nuclear NF-κB translocation. Spironolactone and tempol decreased all markers significantly, whereas hydralazine had just slight effects. These data comprise the first report of essentially blood pressure-independent tissue- and DNA-damaging effects of Ald. A fully activated MR and the production of reactive oxygen and nitrogen species were crucial for these effects.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, 97078 Würzburg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Queisser
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.forename: Valentin
authors.initials: V
authors.lastname: Hey
authors.forename: Samy L
authors.initials: SL
authors.lastname: Habib
authors.forename: Nicole
authors.initials: N
authors.lastname: Schupp
mesh_terms: D000450:Aldosterone / Q000008:administration & dosage* / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000187:drug effects; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000008:administration & dosage; D004249:DNA Damage / Q000187:drug effects; D006830:Hydralazine / Q000008:administration & dosage; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D013113:Spin Labels; D013148:Spironolactone / Q000008:administration & dosage
chemical_list: D003497:Cyclic N-Oxides; D000451:Mineralocorticoid Receptor Antagonists; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D018161:Receptors, Mineralocorticoid; D013113:Spin Labels; D006830:Hydralazine; D013148:Spironolactone; D000450:Aldosterone; C001803:tempol