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Silencing of HIF prolyl-hydroxylase 2 gene in the renal medulla attenuates salt-sensitive hypertension in Dahl S rats.

ABSTRACT: In response to high salt intake, transcription factor hypoxia-inducible factor (HIF) 1? 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-1?, thereby upregulating HIF-1?, and that high salt-induced inhibition in PHD2 and subsequent activation of HIF-1? 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-1? levels in the renal medulla attenuates salt-sensitive hypertension in Dahl S rats.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.PHD2 shRNA reduced PHD2 levels by >60% and significantly increased HIF-1? protein levels and the expression of HIF-1? 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.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.

SUBMITTER: Zhu Q

PROVIDER: S-EPMC3848632 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Silencing of HIF prolyl-hydroxylase 2 gene in the renal medulla attenuates salt-sensitive hypertension in Dahl S rats.

Zhu Qing Q Hu Junping J Han Wei-Qing WQ Zhang Fan F Li Pin-Lan PL Wang Zhengchao Z Li Ningjun N

American journal of hypertension 20131104 1

<h4>Background</h4>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 sa ...[more]

PMID: 24190904

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Project description:Hypertensive cerebropathy is a pathological condition associated with cerebral edema and disruption of the blood-brain barrier. However, the molecular pathways leading to this condition remains obscure. We hypothesize that MMP-9 inhibition can help reducing blood pressure and endothelial disruption associated with hypertensive cerebropathy. Dahl salt-sensitive (Dahl/SS) and Lewis rats were fed with high-salt diet for 6 weeks and then treated without and with GM6001 (MMP inhibitor). Treatment of GM6001 (1.2 mg/kg body weight) was administered through intraperitoneal injections on alternate days for 4 weeks. GM6001 non-administered groups were given vehicle (0.9% NaCl in water) treatment as control. Blood pressure was measured by tail-cuff method. The brain tissues were analyzed for oxidative/nitrosative stress, vascular MMP-9 expression, and tight junction proteins (TJPs). GM6001 treatment significantly reduced mean blood pressure in Dahl/SS rats which was significantly higher in vehicle-treated Dahl/SS rats. MMP-9 expression and activity was also considerably reduced in GM6001-treated Dahl/SS rats, which was otherwise notably increased in vehicle-treated Dahl/SS rats. Similarly MMP-9 expression in cerebral vessels of GM6001-treated Dahl/SS rats was also alleviated, as devised by immunohistochemistry analysis. Oxidative/nitrosative stress was significantly higher in vehicle-treated Dahl/SS rats as determined by biochemical estimations of malondialdehyde, nitrite, reactive oxygen species, and glutathione levels. RT-PCR and immunohistochemistry analysis further confirmed considerable alterations of TJPs in hypertensive rats. Interestingly, GM6001 treatment significantly ameliorated oxidative/nitrosative stress and TJPs, which suggest restoration of vascular integrity in Dahl/SS rats. These findings determined that pharmacological inhibition of MMP-9 in hypertensive Dahl-SS rats attenuate high blood pressure and hypertension-associated cerebrovascular pathology.

Dataset Information

Silencing of HIF prolyl-hydroxylase 2 gene in the renal medulla attenuates salt-sensitive hypertension in Dahl S rats.

Publications

Silencing of HIF prolyl-hydroxylase 2 gene in the renal medulla attenuates salt-sensitive hypertension in Dahl S rats.

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