title: Upregulation of the Na(+)-K(+)-2Cl(-) cotransporter 1 via histone modification in the aortas of angiotensin II-induced hypertensive rats.
abstract: The Na(+)-K(+)-2Cl(-) cotransporter 1 (NKCC1) is upregulated in diverse models of hypertension. We hypothesized that NKCC1 is upregulated via histone modification in the aortas of angiotensin II (Ang II)-induced hypertensive rats. An osmotic mini-pump containing Ang II was implanted in the subcutaneous tissues of the backs of Sprague-Dawley (SD) rats for 7 days. The systolic blood pressure was recorded every day by the tail-cuff method. On days 3 and 7, the mesenteric arteries were excised, cut into rings, mounted in organ baths and subjected to vascular contraction. The levels of Nkcc1 mRNA and protein in the aortas were measured using real-time PCR and Western blotting, respectively. The histone modifications and recruited proteins at the Nkcc1 promoter were determined by chromatin immunoprecipitation. The inhibition of concentration-response curves to phenylephrine by bumetanide, an inhibitor of NKCCs, was greater in Ang II-infused rats than in sham-operated (sham) rats . The levels of Nkcc1 mRNA and protein in the aortas increased gradually as Ang II was infused into the rats. Acetylated histone H3 (H3Ac), an activating histone code, was increased but trimethylated histone H3 at lysine 27 (H3K27me3), a repressive histone code, was greatly decreased in Ang II-infused rats compared with sham. RNA polymerase II was recruited to the Nkcc1 promoter with increased KDM6b. We conclude that the NKCC1 is upregulated via histone modification in the aortas of Ang II-induced hypertensive rats. Thus, we suggest that this ion transporter is epigenetically upregulated by histone modification or DNA demethylation upon the development of hypertension.
authors.affiliation: Department of Pharmacology, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Hyun-Min
authors.initials: HM
authors.lastname: Cho
authors.forename: Dong-Youb
authors.initials: DY
authors.lastname: Lee
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Hae-Ahm
authors.initials: HA
authors.lastname: Lee
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Seok
authors.forename: In Kyeom
authors.initials: IK
authors.lastname: Kim
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure; D015153:Blotting, Western; D002034:Bumetanide / Q000494:pharmacology; D047369:Chromatin Immunoprecipitation; D004232:Diuretics / Q000494:pharmacology; D056466:Histone Demethylases / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D010656:Phenylephrine / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics*; D064506:Solute Carrier Family 12, Member 2; D015854:Up-Regulation; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D004232:Diuretics; D006657:Histones; D012333:RNA, Messenger; C578879:Slc12a2 protein, rat; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D014662:Vasoconstrictor Agents; D002034:Bumetanide; D000804:Angiotensin II; D010656:Phenylephrine; D056466:Histone Demethylases; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase