Overexpression of HIF prolyl-hydoxylase-2 transgene in the renal medulla induced a salt sensitive hypertension.
Renal medullary hypoxia-inducible factor (HIF)-1α and its target genes, such as haem oxygenase and nitric oxide synthase, have been indicated to play an important role in the regulation of sodium excretion and blood pressure. HIF prolyl hydroxylase domain-containing proteins (PHDs) are major enzymes to promote the degradation of HIF-1α. We recently reported that high salt intake suppressed the renal medullary PHD2 expression and thereby activated HIF-1α-mediated gene regulation in the renal medulla in response to high salt. To further define the functional role of renal medullary PHD2 in the regulation of renal adaptation to high salt intake and the longer term control of blood pressure, we transfected PHD2 expression plasmids into the renal medulla in uninephrectomized rats and determined its effects on pressure natriuresis, sodium excretion after salt overloading and the long-term control of arterial pressure after high salt challenge. It was shown that overexpression of PHD2 transgene increased PHD2 levels and decreased HIF-1α levels in the renal medulla, which blunted pressure natriuresis, attenuated sodium excretion, promoted sodium retention and produced salt sensitive hypertension after high salt challenge compared with rats treated with control plasmids. There was no blood pressure change in PHD2-treated rats that were maintained in low salt diet. These results suggested that renal medullary PHD2 is an important regulator in renal adaptation to high salt intake and a deficiency in PHD2-mediated molecular adaptation in response to high salt intake in the renal medulla may represent a pathogenic mechanism producing salt sensitive hypertension.
Department of Pharmacology & Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA.
Qing
Q
Zhu
Miao
M
Liu
Wei-Qing
WQ
Han
Pin-Lan
PL
Li
Zhengchao
Z
Wang
Ningjun
N
Li
D000222:Adaptation, Physiological / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation; D006973:Hypertension / Q000209:etiology / Q000235:genetics*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007679:Kidney Medulla / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009318:Natriuresis / Q000235:genetics; D011312:Pressure; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012964:Sodium / Q000652:urine; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*; D019076:Transgenes
C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017673:Sodium Chloride, Dietary; D012964:Sodium; D011393:Procollagen-Proline Dioxygenase; C580731:Egln1 protein, rat; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases