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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This work was supported in part by grants from the Interdisziplinäres Zentrum für klinische Forschung Erlangen (TP B13), from the Bundesministerium für Bildung und Forschung - Forschung unter Weltraumbedingungen (50WB0620), and from the Deutsche Forschungsgemeinschaft (Ti345/2) to J.T., from the sixth Framework Integrated Project Lymphangiogenomics (LSGH-2004-503573) to D.K., and from a Fresenius Nephro-Core Stipend to A.Z. F.C.L. and D.N.M. were supported by EuReGene; D.N.M. is a Helmholtz fellow. We thank N. Rakova for translating Russian articles and E. Prell, M. Klewer and B. Hausknecht for their technical assistance. We thank P. Uhrin (Department of Vascular Biology and Thrombosis Research, Medical University of Vienna) for the Swiss-129Sv mice and H.M. Kwon (Department of Medicine, University of Maryland) for pCMV-Tag2-TonEBP.
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Machnik, A., Neuhofer, W., Jantsch, J. et al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C–dependent buffering mechanism. Nat Med 15, 545–552 (2009). https://doi.org/10.1038/nm.1960
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