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

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 regulating 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 saltsensitive 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.