Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism.
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.
Department of Nephrology and Hypertension, and Nikolaus Fiebiger Centre for Molecular Medicine, University Clinic and Friedrich Alexander University of Erlangen-Nuremberg, Germany.
Agnes
A
Machnik
Wolfgang
W
Neuhofer
Jonathan
J
Jantsch
Anke
A
Dahlmann
Tuomas
T
Tammela
Katharina
K
Machura
Joon-Keun
JK
Park
Franz-Xaver
FX
Beck
Dominik N
DN
Müller
Wolfgang
W
Derer
Jennifer
J
Goss
Agata
A
Ziomber
Peter
P
Dietsch
Hubertus
H
Wagner
Nico
N
van Rooijen
Armin
A
Kurtz
Karl F
KF
Hilgers
Kari
K
Alitalo
Kai-Uwe
KU
Eckardt
Friedrich C
FC
Luft
Dontscho
D
Kerjaschki
Jens
J
Titze
D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D006706:Homeostasis; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D010586:Phagocytes / Q000187:drug effects / Q000502:physiology; D051381:Rats; D040262:Receptors, Vascular Endothelial Growth Factor / Q000502:physiology; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects; D012879:Skin Physiological Phenomena; D012965:Sodium Chloride / Q000009:adverse effects*; D012982:Sodium, Dietary / Q000009:adverse effects*; D014157:Transcription Factors / Q000502:physiology*; D042582:Vascular Endothelial Growth Factor C / Q000037:antagonists & inhibitors / Q000502:physiology*
C492199:Nfat5 protein, rat; D012982:Sodium, Dietary; D014157:Transcription Factors; D042582:Vascular Endothelial Growth Factor C; D012965:Sodium Chloride; D040262:Receptors, Vascular Endothelial Growth Factor