e-journal

Silencing of HIF Prolyl-Hydroxylase 2 Gene in the Renal Medulla Attenuates Salt-Sensitive Hypertension in Dahl S Rats

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Background
In response to high salt intake, transcription factor hypoxia-inducible factor (HIF) 1α activates many antihypertensive genes, such as heme oxygenase 1 (HO-1) 1 and cyclooxygenase 2 (COX-2) in the renal
medulla, which is an important molecular adaptation to promote extra sodium excretion. We recently showed that high salt inhibited the expression of HIF prolyl-hydroxylase 2 (PHD2), an enzyme that promotes
the degradation of HIF-1α, thereby upregulating HIF-1α, and that high salt–induced inhibition in PHD2 and subsequent activation of HIF-1α in the renal medulla was blunted in Dahl salt-sensitive hypertensive
rats. This study tested the hypothesis that silencing the PHD2 gene to increase HIF-1α levels in the renal medulla attenuates salt-sensitive hypertension in Dahl S rats.

Methods
PHD2 short hairpin RNA (shRNA) plasmids were transfected into the renal medulla in uninephrectomized Dahl S rats. Renal function and blood pressure were then measured.

Results
PHD2 shRNA reduced PHD2 levels by >60% and significantly increased HIF-1α protein levels and the expression of HIF-1α target genes HO-1 and COX-2 by >3-fold in the renal medulla. Functionally, pressure natriuresis was
remarkably enhanced, urinary sodium excretion was doubled after acute intravenous sodium loading, and chronic high salt-induced sodium retention was remarkably decreased, and as a result, salt-sensitive hypertension
was significantly attenuated in PHD2 shRNA rats compared with control rats.

Conclusions
Impaired PHD2 response to high salt intake in the renal medulla may represent a novel mechanism for hypertension in Dahl S rats, and inhibition of PHD2 in the renal medulla could be a therapeutic approach for
salt-sensitive hypertension.

Keywords: blood pressure; cyclooxygenase 2; heme oxygenase 1; hypertension; hypoxia-inducible factor; pressure natriuresis; sodium excretion.

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Informasi Detail

Judul Seri

American Journal of Hypertension

No. Panggil

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Penerbit

: American Journal of Hypertension, Ltd., 2014

Deskripsi Fisik

American Journal of Hypertension 27(1) January 2014

Bahasa

English

ISBN/ISSN

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Klasifikasi

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Tipe Isi

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Tipe Media

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Tipe Pembawa

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Edisi

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Subjek

KESEHATAN

Info Detail Spesifik

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Pernyataan Tanggungjawab

agus

Versi lain/terkait

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