Salt-sensitive hypertension induced by decoy of transcription factor hypoxia-inducible factor-1alpha in the renal medulla.
Hypoxia inducible factor (HIF)-1alpha, a transcription factor, is abundantly expressed in the renal medulla and regulates many oxygen-sensitive genes such as nitric oxide synthase, cyclooxygenase-2, and heme oxygenase-1. Given the important roles of these genes in the control of arterial pressure, the present study was to test the hypothesis that HIF-1alpha-mediated gene activation serves as an antihypertensive pathway by regulating renal medullary function and sodium excretion. HIF-1alpha decoy oligodeoxynucleotides (ODNs) or scrambled ODNs were transfected into the renal medulla in uninephrectomized Sprague-Dawley rats. Two weeks after ODN transfection, the HIF-1alpha binding activities were significantly inhibited by 45%, and high salt-induced increases of nitric oxide synthase-2 and heme oxygenase-1 transcriptions were also inhibited by 70% and 61% in the renal medulla from decoy rats. The natriuretic responses and increases of renal medullary blood flow responding to the elevations of renal perfusion pressure were significantly blunted by 50% and 37% in decoy rats. Intravenously acute sodium loading increased medullary blood flow and urinary sodium excretion, which was remarkably attenuated in decoy rats. In decoy rats, high salt intake caused a greater positive sodium balance. Consequently, arterial pressure was remarkably increased (from 118+/-1.9 to 154+/-6.3 mm Hg) in decoy rats but not in control rats when the rats were challenged with a high salt diet. There was no blood pressure change in decoy rats that were maintained in normal salt diet. In conclusion, HIF-1alpha-mediated gene activation importantly participates in the regulation of renal medullary function and long-term arterial blood pressure.
Li
Ningjun
N
Department of Pharmacology & Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, PO Box 980613, Richmond, VA 23298, USA. nli@vcu.edu
Chen
Li
L
Yi
Fan
F
Xia
Min
M
Li
Pin-Lan
PL
D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D004195:Disease Models, Animal; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007679:Kidney Medulla / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009318:Natriuresis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009841:Oligonucleotides / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow; D012079:Renal Circulation; D017673:Sodium Chloride, Dietary; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014882:Water-Electrolyte Balance
C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009841:Oligonucleotides; D012333:RNA, Messenger; D017673:Sodium Chloride, Dietary; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat