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

被引：783

作者：

Machnik, Agnes ^{[1
]}

Neuhofer, Wolfgang ^{[2
]}

Jantsch, Jonathan ^{[1
,3
]}

Dahlmann, Anke ^{[1
]}

Tammela, Tuomas ^{[4
]}

Machura, Katharina ^{[5
]}

Park, Joon-Keun ^{[6
]}

Beck, Franz-Xaver ^{[2
]}

Mueller, Dominik N. ^{[7
,8
]}

Derer, Wolfgang ^{[9
]}

Goss, Jennifer ^{[1
]}

Ziomber, Agata ^{[1
]}

Dietsch, Peter ^{[10
]}

Wagner, Hubertus ^{[11
]}

van Rooijen, Nico ^{[12
]}

Kurtz, Armin ^{[5
]}

Hilgers, Karl F. ^{[1
]}

Alitalo, Kari ^{[4
]}

Eckardt, Kai-Uwe ^{[1
]}

Luft, Friedrich C. ^{[7
,8
,9
]}

Kerjaschki, Dontscho ^{[13
]}

Titze, Jens ^{[1
]}

机构：

[1] Univ Erlangen Nurnberg, D-8520 Erlangen, Germany

[2] Univ Munich, Dept Physiol, D-8000 Munich, Germany

[3] Univ Clin Erlangen, Inst Clin Microbiol Immunol & Hyg, Erlangen, Germany

[4] Biomedicum Helsinki, Lab Mol Canc Biol, Helsinki, Finland

[5] Univ Regensburg, Inst Physiol, Regensburg, Germany

[6] Hannover Med Sch, Dept Med, Div Nephrol, Hannover, Germany

[7] Max Delbruck Ctr Mol Med, Berlin, Germany

[8] Fac Med Charite, Expt & Clin Res Ctr, Berlin, Germany

[9] HELIOS Klinikum Berlin Brandenburg, Berlin, Germany

[10] Inst Biochem, Berlin, Germany

[11] Max Rubner Inst, Dept Safety & Qual Meat, Kulmbach, Germany

[12] Vrije Univ Amsterdam, Med Ctr, Dept Mol Cell Biol, Amsterdam, Netherlands

[13] Med Univ Vienna, Dept Pathol, Vienna, Austria

来源：

NATURE MEDICINE | 2009年 / 15卷 / 05期

关键词：

NITRIC-OXIDE SYNTHASE; OSMOTICALLY INACTIVE NA+; TUMOR LYMPHANGIOGENESIS; INTERSTITIAL FLOW; SODIUM-BALANCE; DOCA-SALT; VEGF-C; RATS; HYPERTENSION; MICE;

D O I：

10.1038/nm.1960

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：545 / 552

页数：8

共 40 条

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