Tissue-specific upregulation of angiotensin-converting enzyme 1 in spontaneously hypertensive rats through histone code modifications.
The renin-angiotensin system has been implicated in the development of hypertension and damages several organs. The expressions of the components of a local renin-angiotensin system (RAS) in the hypertensive rats differ from those of the normotensive rats. We hypothesized that local tissue-specific upregulation of angiotensin-converting enzyme 1 (ACE1) in hypertension is caused by epigenetic changes. Adrenal gland, aorta, heart, kidney, liver, and lung tissues were excised from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). Ace1 mRNA and protein expressions were measured by real-time PCR and Western blot, respectively. Promoter methylation was revealed by bisulfite sequencing. Histone modifications, such as histone 3 acetylation (H3Ac), fourth lysine trimethylation (H3K4me3), and ninth lysine dimethylation (H3K9me2), were quantified by chromatin immunoprecipitation (ChIP), followed by real-time PCR. The expressions and associations of chromatin remodeling genes were analyzed by real-time PCR and ChIP, respectively. Local tissues from SHRs showed higher expressions of Ace1 mRNA and protein than those from the WKY rats. Ace1 promoter was mostly unmethylated in all of the tissues from both strains. The Ace1 promoter regions of SHR tissues were more enriched with H3Ac and H3K4me3, except in the lungs. The adrenal glands, hearts, and kidneys of SHRs showed less enrichment with H3K9me2. Valsartan treatment in SHRs decreased local Ace1 mRNA and protein expressions, which were accompanied by higher H3K9me2, as well as less H3Ac and H3K4me3. In conclusion, ACE1 is upregulated in local tissues of SHRs via histone code modifications.
Department of Pharmacology, Kyungpook National University School of Medicine, 101 Dongin-2-Ga, Daegu, 700-422 Republic of Korea.
Hae-Ahm
HA
Lee
Hyun-Min
HM
Cho
Dong-Youb
DY
Lee
Kee-Chul
KC
Kim
Hyung Soo
HS
Han
In Kyeom
IK
Kim
D000311:Adrenal Glands / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001794:Blood Pressure; D004195:Disease Models, Animal; D042421:Histone Code; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D060888:Real-Time Polymerase Chain Reaction; D012084:Renin-Angiotensin System / Q000235:genetics*; D015854:Up-Regulation
D012333:RNA, Messenger; D007703:Peptidyl-Dipeptidase A