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Salt-sensitive hypertension induced by decoy of transcription factor hypoxia-inducible factor-1alpha in the renal medulla.

ABSTRACT: Hypoxia inducible factor (HIF)-1alpha, a transcription factor, is abundantly expressed in the renal medulla and regulates many oxygen-sensitive genes such as nitric oxide synthase, cyclooxygenase-2, and heme oxygenase-1. Given the important roles of these genes in the control of arterial pressure, the present study was to test the hypothesis that HIF-1alpha-mediated gene activation serves as an antihypertensive pathway by regulating renal medullary function and sodium excretion. HIF-1alpha decoy oligodeoxynucleotides (ODNs) or scrambled ODNs were transfected into the renal medulla in uninephrectomized Sprague-Dawley rats. Two weeks after ODN transfection, the HIF-1alpha binding activities were significantly inhibited by 45%, and high salt-induced increases of nitric oxide synthase-2 and heme oxygenase-1 transcriptions were also inhibited by 70% and 61% in the renal medulla from decoy rats. The natriuretic responses and increases of renal medullary blood flow responding to the elevations of renal perfusion pressure were significantly blunted by 50% and 37% in decoy rats. Intravenously acute sodium loading increased medullary blood flow and urinary sodium excretion, which was remarkably attenuated in decoy rats. In decoy rats, high salt intake caused a greater positive sodium balance. Consequently, arterial pressure was remarkably increased (from 118+/-1.9 to 154+/-6.3 mm Hg) in decoy rats but not in control rats when the rats were challenged with a high salt diet. There was no blood pressure change in decoy rats that were maintained in normal salt diet. In conclusion, HIF-1alpha-mediated gene activation importantly participates in the regulation of renal medullary function and long-term arterial blood pressure.

SUBMITTER: Li N

PROVIDER: S-EPMC2649696 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Salt-sensitive hypertension induced by decoy of transcription factor hypoxia-inducible factor-1alpha in the renal medulla.

Li Ningjun N Chen Li L Yi Fan F Xia Min M Li Pin-Lan PL

Circulation research 20080320 9

Hypoxia inducible factor (HIF)-1alpha, a transcription factor, is abundantly expressed in the renal medulla and regulates many oxygen-sensitive genes such as nitric oxide synthase, cyclooxygenase-2, and heme oxygenase-1. Given the important roles of these genes in the control of arterial pressure, the present study was to test the hypothesis that HIF-1alpha-mediated gene activation serves as an antihypertensive pathway by regulating renal medullary function and sodium excretion. HIF-1alpha decoy ...[more]

PMID: 18356541

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Project description:BACKGROUND: Hypoxia-inducible factor 1 (HIF-1) is a master transcriptional regulator of genes regulating oxygen homeostasis. The HIF-1 protein is composed of two HIF-1alpha and HIF-1beta/aryl hydrocarbon receptor nuclear translocator (ARNT) subunits. The prognostic relevance of HIF-1alpha protein overexpression has been shown in breast cancer. The impact of HIF-1alpha alternative splice variant expression on breast cancer prognosis in terms of metastasis risk is not well known. METHODS: Using real-time quantitative reverse transcription PCR assays, we measured mRNA concentrations of total HIF-1alpha and 4 variants in breast tissue specimens in a series of 29 normal tissues or benign lesions (normal/benign) and 53 primary carcinomas. In breast cancers HIF-1alpha splice variant levels were compared to clinicopathological parameters including tumour microvessel density and metastasis-free survival. RESULTS: HIF-1alpha isoforms containing a three base pairs TAG insertion between exon 1 and exon 2 (designated HIF-1alphaTAG) and HIF-1alpha736 mRNAs were found expressed at higher levels in oestrogen receptor (OR)-negative carcinomas compared to normal/benign tissues (P = 0.009 and P = 0.004 respectively). In breast carcinoma specimens, lymph node status was significantly associated with HIF-1alphaTAG mRNA levels (P = 0.037). Significant statistical association was found between tumour grade and HIF-1alphaTAG (P = 0.048), and total HIF-1alpha (P = 0.048) mRNA levels. HIF-1alphaTAG mRNA levels were also inversely correlated with both oestrogen and progesterone receptor status (P = 0.005 and P = 0.033 respectively). Univariate analysis showed that high HIF-1alphaTAG mRNA levels correlated with shortened metastasis free survival (P = 0.01). CONCLUSIONS: Our results show for the first time that mRNA expression of a HIF-1alphaTAG splice variant reflects a stage of breast cancer progression and is associated with a worse prognosis.See commentary: http://www.biomedcentral.com/1741-7015/8/45.

Dataset Information

Salt-sensitive hypertension induced by decoy of transcription factor hypoxia-inducible factor-1alpha in the renal medulla.

Publications

Salt-sensitive hypertension induced by decoy of transcription factor hypoxia-inducible factor-1alpha in the renal medulla.

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