A high salt intake has been implicated in cardiovascular disease risk for 5000 years. But salt-sensitive hypertension still remains an enigma. Now, investigators from Germany at the University of Erlangen, the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and Regensburg, collaborating with researchers from Finland and Austria have shed new light on the relationship between salt intake, bodily processes, and blood pressure regulation. Within the skin, they have detected a new storage area for salt in the body. They also found out that if the process behind this storage is defect, animals become hypertensive (Nature Medicine, doi 10.1038/nm.1960)*.
Salt (natrium chloride, NaCl) is required for life. Herbivores (plant-eating animals) risk their lives to go to "salt licks" and carnivores (meat-eating animals) go to salt licks to eat herbivores in order to obtain salt.
Salt is responsible for water regulation in the body. It is taken up by the gastro-intestinal (GI) tract and, in large part, excreted by the kidneys. However, salt is also stored in cells and in the interstitium, the area between cells in the body.
Dr. Jens Titze and colleages, among them Dominik N. Müller, Wolfgang Derer, and Friedrich C. Luft from the Experimental and Clinical Research Center at the MDC, could now show that a high-salt diet in rats leads to the accumulation of salt in the interstitium in the skin. This process is carefully regulated by special white blood cells, the macrophages.
In those macrophages, the scientists found a gene regulator (transcription factor) called TonEBP (tonicity-responsible enhancer binding protein). TonEBP is activated in these cells in response to high salt and turns on a gene (VEGF-C - vascular endothelial growth factor C) that controls the production of lymphatic blood vessels. With high-salt diet the lymphatic vessels increase.
The investigators also showed that when these macrophages are depleted or if the receptor for VEGF-C is absent, the animals are not able to "store their salt" and become hypertensive. However, this process and its relevance to human disease are not yet completely understood..
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
1Department of Nephrology and Hypertension, and Nikolaus Fiebiger Centre for Molecular Medicine, University Clinic and Friedrich Alexander University of Erlangen-Nuremberg, Germany. 2Department of Physiology, University of Munich, Munich, Germany. 3Institute of Clinical Microbiology, Immunology and Hygiene, University Clinic of Erlangen, Germany. 4Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, Helsinki, Finland. 5Institute of Physiology, University Regensburg, Regensburg, Germany. 6Division of Nephrology, Department of Medicine, Hannover Medical School, Germany. 7Max Delbrück Center for Molecular Medicine and Experimental and Clinical Research Center, Medical Faculty of the Charité, Berlin, Germany. 8HELIOS Klinikum Berlin-Brandenburg, Berlin, Germany. 9Institute of Biochemistry, Charité Campus Benjamin Franklin, Berlin, Germany. 10Department of Safety and Quality of Meat, Max Rubner–Institute, Kulmbach, Germany. 11Department of Molecular Cell Biology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. 12Department of Pathology, Medical University Vienna, Vienna, Austria.
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