![]() ![]() The kidney is still seen as the key controller of total body sodium and extracellular volume homeostasis. It is known that the sensitivity of blood pressure to salt among individuals is variable. But, while not mentioned by the authors, this sodium buffering capacity of the skin possibly also affects some important functions of the skin. The sodium buffering capacity of the skin is obviously the key explaining why some people with respect to blood pressure regulation are salt sensitive and others are not. This study gives us a complete new understanding of mononuclear phagocyte system cell and lymphatic function in the context of interstitial sodium homeostasis and blood pressure regulation. This study draws an entirely new scenario for the interpretation of hypertension, particularly hypertension secondary to chronic kidney disease (CKD) and for cardiovascular diseases in general. Of note this mechanism may be operative in humans in that circulating levels of VEGF-C are high in hypertensive patients. Indeed macrophage depletion or VEGF-C inhibition leads to a greater BP rise in response to high sodium. Remarkably this pathway is important in BP control. In macrophages in culture, hypertonicity enhances the production of a protein (tonicity enhanced binding protein,TonEBP) which activates VEGF-C expression. Stimulated by (sodium driven) local hypertonicity this inflammatory cell synthesises vascular endothelial growth factor-C (VEGF-C) which in turn stimulates lymphatic vessel growth thereby generating a third space that limits the increase in body sodium and blunts the BP increase that would be otherwise caused by high salt intake. In this study the macrophage emerges as an important player in salt metabolism. ![]() The kidney, by matching sodium excretion to the daily sodium intake, keeps extracellular fluid volume and thus blood pressure constant and that this phenomenon engenders local hypertonicity. Sodium is the main osmotic constituent of extracellular fluid volume, which consist of vascular and interstitial fluids. This paper completely challenges the classical concept of blood pressure regulation by introducing the interstitial fluid of the skin as an active player and by suggesting that, like obesity, hypertension might involve dysregulation of the immune system. They demonstrate also that this regulation is a critical determinant of extracellular fluid and blood pressure regulation. demonstrates in this paper that the interstitial fluid is a compartment which composition and volume are tightly and specifically regulated by osmo-dependent release of VEGF-C by macrophage cells. 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. 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. 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. 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. 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. ![]() 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. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |