Lysine-specific demethylase-1 modifies the age effect on blood pressure sensitivity to dietary salt intake.
How interactions of an individual's genetic background and environmental factors, such as dietary salt intake, result in age-associated blood pressure elevation is largely unknown. Lysine-specific demethylase-1 (LSD1) is a histone demethylase that mediates epigenetic regulation and modification of gene transcription. We have shown previously that hypertensive African-American minor allele carriers of the LSD1 single nucleotide polymorphism (rs587168) display blood pressure salt sensitivity. Our goal was to further examine the effects of LSD1 genotype variants on interactions between dietary salt intake, age, and blood pressure. We found that LSD1 single nucleotide polymorphism (rs7548692) predisposes to increasing salt sensitivity during aging in normotensive Caucasian subjects. Using a LSD1 heterozygous knockout mouse model, we compared blood pressure values on low (0.02 % Na(+)) vs. high (1.6 % Na(+)) salt intake. Our results demonstrate significantly increased blood pressure salt sensitivity in LSD1-deficient compared to wild-type animals with age, confirming our findings of salt sensitivity in humans. Elevated blood pressure in LSD1(+/-) mice is associated with total plasma volume expansion and altered renal Na(+) excretion. In summary, our human and animal studies demonstrate that LSD1 is a genetic factor that interacts with dietary salt intake modifying age-associated blood pressure increases and salt sensitivity through alteration of renal Na(+) handling.
Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA, alexander.krug@t-online.de.
Alexander W
AW
Krug
Eric
E
Tille
Bei
B
Sun
Luminita
L
Pojoga
Jonathan
J
Williams
Bindu
B
Chamarthi
Andrew H
AH
Lichtman
Paul N
PN
Hopkins
Gail K
GK
Adler
Gordon H
GH
Williams
D000328:Adult; D000368:Aged; D000375:Aging / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D056466:Histone Demethylases / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D012982:Sodium, Dietary / Q000008:administration & dosage* / Q000009:adverse effects; D055815:Young Adult
D012982:Sodium, Dietary; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; C495195:KDM1A protein, human; D010089:Oxidoreductases, N-Demethylating