Epidemiological studies exploring the connection between hypertension and cancer demonstrate a higher cancer incidence, especially of kidney cancer, and a higher cancer mortality in hypertensive patients. Hormones elevated in hypertension, i.e., aldosterone and angiotensin II, which exert genotoxic effects in vitro, could contribute to carcinogenesis in hypertension. The present study was conducted to investigate the possible DNA-damaging effect of aldosterone receptor activation in vivo. Crl:CD (Sprague-Dawley) rats were treated for 6 wk with desoxycorticosterone acetate (DOCA) and salt to induce a mineralocorticoid-dependent hypertension. DOCA-salt treatment caused increased blood pressure (؉26 mmHg) compared to untreated rats, elevated markers of kidney failure (up to 62-fold for Kim-1), and the induction of several proinflammatory genes and proteins (up to 2.6-fold for tissue MCP-1). The mineralocorticoid receptor (MR) antagonist spironolactone (MR IC 50 24 nM) and the novel nonsteroidal antagonist BR-4628 (MR IC 50 28 nM) decreased these damage markers. DOCA-salt treatment also caused 8.8-fold increased structural DNA damage, determined with the comet assay, double-strand breaks (3.5-fold), detected immunohistochemically, and oxidative stress. Furthermore, the oxidatively modified mutagenic DNA base 7,8-dihydro-8-oxoguanine (8-oxodG), quantified by LC-MS/MS, was almost 2-fold higher in DOCA-salt-treated kidneys. Our results suggest a mutagenic potential of high mineralocorticoid levels, frequent in hypertensive individuals.-Schupp, N., Kolkhof, P., Queisser, N., Gärtner, S., Schmid, U., Kretschmer, A., Hartmann, E., Oli, R G., Schäfer, S., Stopper, H. Mineralocorticoid receptor-mediated DNA damage in kidneys of DOCA-salt hypertensive rats. FASEB J. 25, 968 -978 (2011). www.fasebj.org Key Words: 8-oxodG ⅐ double-strand breaks ⅐ hypertension ⅐ oxidative DNA damage ⅐ oxidative stressAldosterone is produced in the adrenal zona glomerulosa on stimulation by angiotensin II, potassium, or the adrenocorticotropic hormone. Classically, it regulates sodium excretion and thereby blood pressure homeostasis through mineralocorticoid receptor (MR) dependent, genomic effects in the distal nephron of the kidney. Together with angiotensin II, it is the major effector of the renin-angiotensin-aldosterone system. Recent studies suggest that 10 -15% of hypertensive individuals have an elevated aldosterone to renin ratio, a biochemical measure for hyperaldosteronism (1). The plasma concentration of aldosterone in these patients ranges from 0.5 to 6.3 nM, with patients suffering from congestive heart failure reaching 8 nM (2, 3). Studies demonstrating the effectiveness of MR antagonism in patients with resistant hypertension, also support the high prevalence (20%) of hyperaldosteronism in this population (1, 4). Aldosterone plays an important role in the pathophysiology of heart failure. Clinical trials examining the effect of combined angiotensin converting enzyme (ACE) inhibition and MR antagonism showed a reduction of mortalit...