title: Silencing of HIF prolyl-hydroxylase 2 gene in the renal medulla attenuates salt-sensitive hypertension in Dahl S rats.
abstract: BACKGROUND
  In response to high salt intake, transcription factor hypoxia-inducible factor (HIF) 1α activates many antihypertensive genes, such as heme oxygenase 1 (HO-1) 1 and cyclooxygenase 2 (COX-2) in the renal medulla, which is an important molecular adaptation to promote extra sodium excretion. We recently showed that high salt inhibited the expression of HIF prolyl-hydroxylase 2 (PHD2), an enzyme that promotes the degradation of HIF-1α, thereby upregulating HIF-1α, and that high salt-induced inhibition in PHD2 and subsequent activation of HIF-1α in the renal medulla was blunted in Dahl salt-sensitive hypertensive rats. This study tested the hypothesis that silencing the PHD2 gene to increase HIF-1α levels in the renal medulla attenuates salt-sensitive hypertension in Dahl S rats.
  
  
  METHODS
  PHD2 short hairpin RNA (shRNA) plasmids were transfected into the renal medulla in uninephrectomized Dahl S rats. Renal function and blood pressure were then measured.
  
  
  RESULTS
  PHD2 shRNA reduced PHD2 levels by >60% and significantly increased HIF-1α protein levels and the expression of HIF-1α target genes HO-1 and COX-2 by >3-fold in the renal medulla. Functionally, pressure natriuresis was remarkably enhanced, urinary sodium excretion was doubled after acute intravenous sodium loading, and chronic high salt-induced sodium retention was remarkably decreased, and as a result, salt-sensitive hypertension was significantly attenuated in PHD2 shRNA rats compared with control rats.
  
  
  CONCLUSIONS
  Impaired PHD2 response to high salt intake in the renal medulla may represent a novel mechanism for hypertension in Dahl S rats, and inhibition of PHD2 in the renal medulla could be a therapeutic approach for salt-sensitive hypertension.
authors.affiliation: Department of Pharmacology & Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhu
authors.forename: Junping
authors.initials: J
authors.lastname: Hu
authors.forename: Wei-Qing
authors.initials: WQ
authors.lastname: Han
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Pin-Lan
authors.initials: PL
authors.lastname: Li
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Wang
authors.forename: Ningjun
authors.initials: N
authors.lastname: Li
mesh_terms: D000818:Animals; D001794:Blood Pressure; D004195:Disease Models, Animal; D015536:Down-Regulation; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods*; D006973:Hypertension / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics / Q000378:metabolism*; D007679:Kidney Medulla / Q000098:blood supply / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D009318:Natriuresis; D034741:RNA, Small Interfering / Q000378:metabolism*; D051381:Rats; D020303:Rats, Inbred Dahl; D012079:Renal Circulation; D017673:Sodium Chloride, Dietary; D013997:Time Factors; D014162:Transfection
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D017673:Sodium Chloride, Dietary; C580731:Egln1 protein, rat; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
keywords: blood pressure; cyclooxygenase 2; heme oxygenase 1; hypertension; hypoxia-inducible factor; pressure natriuresis; sodium excretion.