Lymphangiogenesis in response to osmotically inactive Na+ storage in the skin
Final Report Abstract
We have demonstrated that the skin interstitium sequesters excess Na+ and Cl‐ in salt‐ sensitive hypertension. Mononuclear phagocyte system (MPS) cells are recruited to the skin, sense the hypertonic electrolyte accumulation in skin, and enhance electrolyte clearance via cutaneous lymph vessels by secreting vascular endothelial growth factor C (VEGF‐C). First, we show that deletion of tonicity‐enhancer binding protein (TonEBP) in MPS cells prevents the cutaneous lymph capillary response and increases blood pressure. This finding defines “homeostatic immune function” as a process by which immune cells regulate local tissue electrolyte homeostasis and systemic blood pressure. Second, we show that pharmacological blockade of this immune‐cell driven lymph capillary response leads to salt‐sensitive hypertension, defining “lymphatic regulation of blood pressure”. Third, we show that skin‐specific depletion of immune‐cell derived VEGF‐C leads to skin electrolyte accumulation and blood pressure increase. This finding supports the idea that besides renal mechanisms, immune‐driven extrarenal regulatory mechanisms for electrolyte homeostasis are important for systemic blood pressure control. The emerging concept of Na+ storage opens new questions for basic researchers and clinician‐scientists. Some straightforward clinical questions are whether humans with increased Na+ storage are at risk for developing cardiovascular disease and whether tissue Na+ content can be modified by life‐style changes or medical treatment. To address this question, we have implemented 23NaMRI technology to quantitatively and non‐invasively visualize Na+ reservoirs in humans. Seeing the Na+ in humans is a new conceptual approach to provide answers.
Publications
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Macrophages regulate salt‐dependent volume and blood pressure by a vascular endothelial growth factor‐C‐dependent buffering mechanism. Nat Med.2009;15:545‐552
Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Machura K, Park JK, Beck FX, Muller DN, Derer W, Goss J, Ziomber A, Dietsch P, Wagner H, van Rooijen N, Kurtz A, Hilgers KF, Alitalo K, Eckardt KU, Luft FC, Kerjaschki D, Titze J
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Mononuclear phagocyte system depletion blocks interstitial tonicity‐responsive enhance binding protein/vascular endothelial growth factor C expression and induces salt‐sensitive hypertension in rats. Hypertension. 2010;55:755‐761
Machnik A, Dahlmann A, Kopp C, Goss J, Wagner H, van Rooijen N, Eckardt KU, Muller DN, Park JK, Luft FC, Kerjaschki D, Titze J
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23Na magnetic resonance imaging of tissue sodium. Hypertension. 2012;59:167‐172
Kopp C, Linz P, Wachsmuth L, Dahlmann A, Horbach T, Schöfl C, Renz W, Santoro D, Niendorf T, Müller DN, Neininger M, Cavallaro A, Eckardt KU, Schmieder RE, Luft FC, Uder M, Titze J
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Seeing the sodium in a patient with hypernatremia. Kidney Int. 2012;82:1343‐1344
Kopp C, Linz P, Hammon M, Schofl C, Grauer M, Eckardt KU, Cavallaro A, Uder M, Luft FC, Titze J
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23Na magnetic resonance imaging‐determined tissue sodium in healthy subjects and hypertensive patients. Hypertension. 2013 61:635‐640
Kopp C, Linz P, Dahlmann A, Hammon M, Jantsch J, Müller DN, Schmieder RE, Cavallaro A, Eckardt KU, Uder M, Luft FC, Titze J
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Long‐term space flight simulation reveals infradian rhythmicity in human Na+ balance. Cell Metab. 2013;17:125‐131
Rakova N, Jüttner K, Dahlmann A, Schröder A, Linz P, Kopp C, Rauh M, Goller U, Beck L, Agureev A, Vassilieva G, Lenkova L, Johannes B, Wabel P, Moissl U, Vienken J, Gerzer R, Eckardt KU, Müller DN, Kirsch KA, Morukov B, Luft FC, Titze J
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Sodium chloride drives autoimmune disease by the induction of pathogenic th17 cells. Nature. 2013; Mar 6
Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, Müller DN, Hafler DA
