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Hypoxia-inducible factor prolyl-hydroxylase 2 senses high-salt intake to increase hypoxia inducible factor 1alpha levels in the renal medulla.

ABSTRACT: High salt induces the expression of transcription factor hypoxia-inducible factor (HIF) 1alpha and its target genes in the renal medulla, which is an important renal adaptive mechanism to high-salt intake. HIF prolyl-hydroxylase domain-containing proteins (PHDs) have been identified as major enzymes to promote the degradation of HIF-1alpha. PHD2 is the predominant isoform of PHDs in the kidney and is primarily expressed in the renal medulla. The present study tested the hypothesis that PHD2 responds to high salt and mediates high-salt-induced increase in HIF-1alpha levels in the renal medulla. In normotensive rats, high-salt intake (4% NaCl, 10 days) significantly inhibited PHD2 expressions and enzyme activities in the renal medulla. Renal medullary overexpression of the PHD2 transgene significantly decreased HIF-1alpha levels. PHD2 transgene also blocked high-salt-induced activation of HIF-1alpha target genes heme oxygenase 1 and NO synthase 2 in the renal medulla. In Dahl salt-sensitive hypertensive rats, however, high-salt intake did not inhibit the expression and activities of PHD2 in the renal medulla. Correspondingly, renal medullary HIF-1alpha levels were not upregulated by high-salt intake in these rats. After transfection of PHD2 small hairpin RNA, HIF-1alpha and its target genes were significantly upregulated by high-salt intake in Dahl salt-sensitive rats. Overexpression of PHD2 transgene in the renal medulla impaired renal sodium excretion after salt loading. These data suggest that high-salt intake inhibits PHD2 in the renal medulla, thereby upregulating the HIF-1alpha expression. The lack of PHD-mediated response to high salt may represent a pathogenic mechanism producing salt-sensitive hypertension.

SUBMITTER: Wang Z

PROVIDER: S-EPMC2897146 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Hypoxia-inducible factor prolyl-hydroxylase 2 senses high-salt intake to increase hypoxia inducible factor 1alpha levels in the renal medulla.

Wang Zhengchao Z Zhu Qing Q Xia Min M Li Pin-Lan PL Hinton Shante J SJ Li Ningjun N

Hypertension (Dallas, Tex. : 1979) 20100322 5

High salt induces the expression of transcription factor hypoxia-inducible factor (HIF) 1alpha and its target genes in the renal medulla, which is an important renal adaptive mechanism to high-salt intake. HIF prolyl-hydroxylase domain-containing proteins (PHDs) have been identified as major enzymes to promote the degradation of HIF-1alpha. PHD2 is the predominant isoform of PHDs in the kidney and is primarily expressed in the renal medulla. The present study tested the hypothesis that PHD2 resp ...[more]

PMID: 20308610

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Project description:BackgroundThe endothelin B receptor (ET(B)R) promotes tumorigenesis and melanoma progression through activation by endothelin (ET)-1, thus representing a promising therapeutic target. The stability of hypoxia-inducible factor (HIF)-1alpha is essential for melanomagenesis and progression, and is controlled by site-specific hydroxylation carried out by HIF-prolyl hydroxylase domain (PHD) and subsequent proteosomal degradation.Principal findingsHere we found that in melanoma cells ET-1, ET-2, and ET-3 through ET(B)R, enhance the expression and activity of HIF-1alpha and HIF-2alpha that in turn regulate the expression of vascular endothelial growth factor (VEGF) in response to ETs or hypoxia. Under normoxic conditions, ET-1 controls HIF-alpha stability by inhibiting its degradation, as determined by impaired degradation of a reporter gene containing the HIF-1alpha oxygen-dependent degradation domain encompassing the PHD-targeted prolines. In particular, ETs through ET(B)R markedly decrease PHD2 mRNA and protein levels and promoter activity. In addition, activation of phosphatidylinositol 3-kinase (PI3K)-dependent integrin linked kinase (ILK)-AKT-mammalian target of rapamycin (mTOR) pathway is required for ET(B)R-mediated PHD2 inhibition, HIF-1alpha, HIF-2alpha, and VEGF expression. At functional level, PHD2 knockdown does not further increase ETs-induced in vitro tube formation of endothelial cells and melanoma cell invasiveness, demonstrating that these processes are regulated in a PHD2-dependent manner. In human primary and metastatic melanoma tissues as well as in cell lines, that express high levels of HIF-1alpha, ET(B)R expression is associated with low PHD2 levels. In melanoma xenografts, ET(B)R blockade by ET(B)R antagonist results in a concomitant reduction of tumor growth, angiogenesis, HIF-1alpha, and HIF-2alpha expression, and an increase in PHD2 levels.ConclusionsIn this study we identified the underlying mechanism by which ET-1, through the regulation of PHD2, controls HIF-1alpha stability and thereby regulates angiogenesis and melanoma cell invasion. These results further indicate that targeting ET(B)R may represent a potential therapeutic treatment of melanoma by impairing HIF-1alpha stability.

Dataset Information

Hypoxia-inducible factor prolyl-hydroxylase 2 senses high-salt intake to increase hypoxia inducible factor 1alpha levels in the renal medulla.

Publications

Hypoxia-inducible factor prolyl-hydroxylase 2 senses high-salt intake to increase hypoxia inducible factor 1alpha levels in the renal medulla.

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