期刊
NATURE MEDICINE
卷 15, 期 5, 页码 545-552出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.1960
关键词
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资金
- Interdisziplinares Zentrum fur klinische Forschung Erlangen [TP B13]
- Bundesministerium fur Bildung und Forschung - Forschung unter Weltraumbedingungen [50WB0620]
- Deutsche Forschungsgemeinschaft [Ti345/2]
- sixth Framework Integrated Project Lymphangiogenomics [LSGH-2004-503573]
- EuReGene
In salt-sensitive hypertension, the accumulation of Na(+) in tissue has been presumed to be accompanied by a commensurate retention of water to maintain the isotonicity of body fluids. We show here that a high-salt diet (HSD) in rats leads to interstitial hypertonic Na(+) accumulation in skin, resulting in increased density and hyperplasia of the lymphcapillary network. The mechanisms underlying these effects on lymphatics involve activation of tonicity-responsive enhancer binding protein (TonEBP) in mononuclear phagocyte system (MPS) cells infiltrating the interstitium of the skin. TonEBP binds the promoter of the gene encoding vascular endothelial growth factor-C (VEGF-C, encoded by Vegfc) and causes VEGF-C secretion by macrophages. MPS cell depletion or VEGF-C trapping by soluble VEGF receptor-3 blocks VEGF-C signaling, augments interstitial hypertonic volume retention, decreases endothelial nitric oxide synthase expression and elevates blood pressure in response to HSD. Our data show that TonEBP-VEGF-C signaling in MPS cells is a major determinant of extracellular volume and blood pressure homeostasis and identify VEGFC as an osmosensitive, hypertonicity-driven gene intimately involved in salt-induced hypertension.
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