Gene silencing of HIF prolyl‐hydroxylase 2 in the renal medulla attenuated sodium retention in Dahl S Rats

Abstract

We previously showed that high salt intake (HS) inhibited HIF prolyl‐hydroxylase 2 (PHD2), an enzyme that promotes the degradation of hypoxia inducible factor (HIF)‐1α, and upregulated HIF‐1α and its target genes nitric oxide synthase (NOS)2 and heme oxygenase (HO)‐1 in the renal medulla, which stimulated the excretion of extra sodium load. This HS‐induced inhibition in PHD2 was not observed in Dahl Salt‐sensitive hypertensive (DS) rats. The present study determined whether silencing PHD2 gene would increase the levels of HIF‐1α and its target genes in the renal medulla, consequently enhancing the sodium excretion in DS rats. PHD2‐shRNA plasmid was transfected into the renal medulla in uninephrectomized DS rats. Ten days after the transfection PHD2 mRNA levels were decreased by 60% and the expression of HIF‐1α target genes NOS2 and HO‐1 were increased by >2 folds in the renal medulla. Functionally, urinary sodium excretion in PHD2‐shRNA rats was doubled compared with control after acute IV sodium loading. Furthermore, chronic HS‐induced sodium retention was remarkably attenuated in PHD2‐shRNA rats. It is suggested that impaired PHD2 response to high salt in the renal medulla may represent a novel mechanism for hypertension in DS rats and that inhibition of PHD2 in the renal medulla could be a therapeutic approach for salt‐sensitive hypertension. (support: NIH grants HL89563, HL106042 and DK54927).