title: Expression of Na+-K+ -2Cl- cotransporter 1 is epigenetically regulated during postnatal development of hypertension.
abstract: BACKGROUND
  The expression of Na(+)-K(+)-2Cl(-) cotransporter 1 (NKCC1) is upregulated in spontaneously hypertensive rat (SHR). We investigated whether expression of NKCC1 is epigenetically regulated during postnatal development of hypertension.
  
  
  METHODS
  The mesenteric arteries from 5-, 10-, and 18-week-old Wistar-Kyoto rats (WKY) and SHRs were subjected to vascular contraction. We determined expression levels of Nkcc1 mRNA and protein, methylation status, and histone modification of Nkcc1 promoter, and DNA methyltransferase (DNMT) activity.
  
  
  RESULTS
  The inhibition of dose-response curves by bumetanide, an inhibitor of NKCC1, as well as the expression of Nkcc1 mRNA and protein was comparable between 5-week-old SHR and age-matched WKY, but greater in 18-week-old SHR than in age-matched WKY. Nkcc1 promoter in WKY was getting methylated with age whereas that in SHR mostly remained hypomethylated after development of hypertension. DNMT3B was highly associated with the promoter of WKY, whereas the CXXC finger protein 1 (Cfp1) was highly bound to the promoter of SHR. At the age of 18 weeks, the DNMT activity in aorta of WKY was about threefold higher than that of SHR. The transcription-activating histone code acetyl H3 was higher in SHR than in WKY, whereas suppressive histone code dimethyl H3K9 was greater in WKY than in SHR.
  
  
  CONCLUSIONS
  It is concluded that expression of NKCC1 is epigenetically upregulated during postnatal development of hypertension. Our data indicate that maintenance of hypomethylation in Nkcc1 promoter of SHR resulting from low DNMT activity plays an important role in the upregulation of NKCC1 during development of spontaneous 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: Hae-Ahm
authors.initials: HA
authors.lastname: Lee
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Hyung Soo
authors.initials: HS
authors.lastname: Han
authors.forename: In Kyeom
authors.initials: IK
authors.lastname: Kim
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D002034:Bumetanide / Q000494:pharmacology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D057890:Epigenomics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology; D011401:Promoter Regions, Genetic; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D028021:Sodium-Potassium-Chloride Symporters / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D064506:Solute Carrier Family 12, Member 2; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: C570704:CXXC1 protein, rat; D006657:Histones; C578879:Slc12a2 protein, rat; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D015534:Trans-Activators; D002034:Bumetanide; D004248:DNA (Cytosine-5-)-Methyltransferases