Blood pressure has only minor influence on aldosterone-induced oxidative stress and DNA damage in vivo.

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.