Aldosterone causes DNA strand breaks and chromosomal damage in renal cells, which are prevented by mineralocorticoid receptor antagonists.
Epidemiological studies exploring the connection between hypertension and cancer incidence find a higher cancer mortality in hypertensive patients, particularly elevated in hypertension associated with a stimulation of the renin-angiotensin-aldosterone system. Primary aldosteronism, with plasma aldosterone levels between 0.5 and 1 nM (18-36 ng/dL) and local aldosterone levels up to 500 nM (18,000 ng/dL), is now recognised as a more common cause for hypertension. We recently found angiotensin II to be genotoxic due to its induction of oxidative stress. Since aldosterone in higher concentrations also has oxidative effects, its potential genotoxic action in pig LLC-PK1 cells with properties of proximal tubules was analysed. DNA damage was evaluated by two test systems: the comet assay, and the micronucleus frequency test. The results showed that aldosterone concentrations starting from 10 nM (360 ng/dL) caused a significant increase of DNA damage monitored with the comet assay in LLC-PK1, while there was no change in cell vitality and proliferation. The micronucleus frequency test revealed that 10 nM aldosterone also leads to the formation of micronuclei. Furthermore, the formation of superoxide radicals in the cells by this aldosterone concentration could be detected with the superoxide-specific stain dihydroethidium. Further evidence for oxidative stress-induced DNA damage was its reversibility by the antioxidants tempol and catalase. Addition of the steroidal mineralocorticoid receptor antagonist spironolactone or the novel selective nonsteroidal antagonist (R)-BR-4628 reduced the DNA damage and the amount of superoxide radicals indicating a receptor-dependent process.
Schupp
N
N
Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany. nicole.schupp@toxi.uni-wuerzburg.de
Queisser
N
N
Wolf
M
M
Kolkhof
P
P
Bärfacker
L
L
Schäfer
S
S
Heidland
A
A
Stopper
H
H
D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D002875:Chromosomes / Q000187:drug effects*; D020552:Comet Assay; D019610:Cytoprotection / Q000187:drug effects*; D053960:DNA Breaks / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006727:Hormone Antagonists / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D015162:Micronucleus Tests; D015735:Mifepristone / Q000494:pharmacology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D013148:Spironolactone / Q000494:pharmacology; D013552:Swine
C000608139:BR-4628; D002867:Chromones; D004095:Dihydropyridines; D006727:Hormone Antagonists; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D015735:Mifepristone; D000450:Aldosterone