Mineralocorticoid receptor-mediated DNA damage in kidneys of DOCA-salt hypertensive rats.
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-oxo-guanine (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.
Institute of Pharmacology and Toxicology, University of Würzburg, 97078 Würzburg, Germany. nicole.schupp@toxi.uni-wuerzburg.de
Nicole
N
Schupp
Peter
P
Kolkhof
Nina
N
Queisser
Sabine
S
Gärtner
Ursula
U
Schmid
Axel
A
Kretschmer
Elke
E
Hartmann
Rajaraman G
RG
Oli
Stefan
S
Schäfer
Helga
H
Stopper
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000502:physiology*; D003900:Desoxycorticosterone / Q000633:toxicity; D004195:Disease Models, Animal; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006977:Hypertension, Renal / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D008901:Mineralocorticoids / Q000633:toxicity; D009392:Nephrectomy; D009393:Nephritis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D013148:Spironolactone / Q000494:pharmacology
D000451:Mineralocorticoid Receptor Antagonists; D008901:Mineralocorticoids; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D003900:Desoxycorticosterone; C024829:8-hydroxyguanine; D006147:Guanine