Article abstract

Nature Medicine 15, 545 - 552 (2009)
Published online: 3 May 2009 | doi:10.1038/nm.1960

Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C–dependent buffering mechanism

Agnes Machnik1, Wolfgang Neuhofer2, Jonathan Jantsch1,3, Anke Dahlmann1, Tuomas Tammela4, Katharina Machura5, Joon-Keun Park6, Franz-Xaver Beck2, Dominik N Müller7, Wolfgang Derer8, Jennifer Goss1, Agata Ziomber1, Peter Dietsch9, Hubertus Wagner10, Nico van Rooijen11, Armin Kurtz5, Karl F Hilgers1, Kari Alitalo4, Kai-Uwe Eckardt1, Friedrich C Luft7,8, Dontscho Kerjaschki12 & Jens Titze1

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.

  1. Department of Nephrology and Hypertension, and Nikolaus Fiebiger Centre for Molecular Medicine, University Clinic and Friedrich Alexander University of Erlangen-Nuremberg, Germany.
  2. Department of Physiology, University of Munich, Munich, Germany.
  3. Institute of Clinical Microbiology, Immunology and Hygiene, University Clinic of Erlangen, Germany.
  4. Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, Helsinki, Finland.
  5. Institute of Physiology, University Regensburg, Regensburg, Germany.
  6. Division of Nephrology, Department of Medicine, Hannover Medical School, Germany.
  7. Max Delbrück Center for Molecular Medicine and Experimental and Clinical Research Center, Medical Faculty of the Charité, Berlin, Germany.
  8. HELIOS Klinikum Berlin-Brandenburg, Berlin, Germany.
  9. Institute of Biochemistry, Charité Campus Benjamin Franklin, Berlin, Germany.
  10. Department of Safety and Quality of Meat, Max Rubner–Institute, Kulmbach, Germany.
  11. Department of Molecular Cell Biology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
  12. Department of Pathology, Medical University Vienna, Vienna, Austria.

Correspondence to: Jens Titze1 e-mail:


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