Am J Cardiovasc Dis 2012;2(3):208-215

Review Article
Hypoxia inducible factor-1α-mediated gene activation in the regulation of
renal medullary function and salt sensitivity of blood pressure

Ningjun Li

Department of Pharmacology & Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University,
Richmond, VA 23298

Received June 11, 2012; accepted July 11, 2012; Epub July 25, 2012; Published August 15, 2012

Abstract: Many enzymes that produce natriuretic factors such as nitric oxide synthase (NOS), hemeoxygenase-1 (HO-1)
and cyclooxygenase-2 (COX-2) are highly expressed in the renal medulla. These enzymes in the renal medulla are up-
regulated in response to high salt intake. Inhibition of these enzymes within the renal medulla reduces sodium excretion
and increases salt sensitivity of arterial blood pressure, indicating that these enzymes play important roles in kidney salt
handling and renal adaptation to high salt challenge. However, it remains a question what mechanisms mediate the
activation of these enzymes in response to high salt challenge in the renal medulla. Interestingly, these enzymes are
oxygen sensitive genes and regulated by transcription factor hypoxia-inducible factor (HIF)-1α. Our recent serial studies
have demonstrated that: 1) High salt intake stimulates HIF-1α-mediated gene expression, such as NOS, HO-1 and COX-2,
in the renal medulla, which may augment the production of different antihypertensive factors in the renal medulla,
mediating renal adaptation to high salt intake and regulates salt sensitivity of arterial blood pressure. 2) HIF prolyl-
hydroxylase 2 (PHD2), an enzyme that promotes the degradation of HIF-1α, is highly expressed in renal medulla. High salt
intake suppresses the expression of PHD2 in the renal medulla, which increases HIF-1α-mediated gene expressions in
the renal medulla, thereby participates in the control of salt sensitivity of blood pressure. 3) The high salt-induced inhibition
in PHD2 and the consequent activation of HIF-1α in the renal medulla is not observed in Dahl salt sensitive hypertensive
(Dahl/ss) rats. Correction of these defects in PHD2/HIF-1α-associated molecular adaptation in the renal medulla improves
sodium excretion, reduces sodium retention and attenuates salt-sensitive hypertension in Dahl/ss rats. In conclusion,
PHD2 regulation of HIF-1α-mediated gene activation in the renal medulla is an important molecular adaptation to high salt
intake; impaired PHD2 regulation of HIF-1α-mediated gene activation in the renal medulla may be responsible for the salt-
sensitive hypertension in Dahl/ss rats; correction of these defects may be used to as therapeutic strategies for the
treatment of salt-sensitive hypertension. (AJCD1206002).

Keywords: Salt sensitive hypertension, gene transfection, Dahl S rat, pressure natriuresis, hypoxia inducible factor-1α,
transcription factor, sodium excretion, heme oxygenase-1, cyclooxygenase-2, fluid homeostasis

Address all correspondence to:
Dr. Ningjun Li
Department of Pharmacology & Toxicology
Medical College of Virginia Campus
Virginia Commonwealth University
P.O. Box  980613, Richmond
VA 23298, USA.
Tel: (804) 828-2071; Fax: (804) 828-4794
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