Blood pressure control: salt gets under your skin

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n e w s a n d v i e w sBlood pressure control: salt gets under your skinPaul J Marvar, Frank J Gordon & David G HarrisonAfter an increase in dietary salt, the excess sodium is stored under the skinstimulating lymphatic growth through the activity of macrophages (pages 545552). The findings should recast thinking about how blood pressure is regulated.Paul J. Marvar and David G. Harrison are in the Department of Medicine Division of Cardiology, and Frank J. Gordon is in the Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, USA. e-mail: dharr02@emory.eduIf you ask a physiologist what organs are involved in blood pressure regulation, you will probably be told the kidney, the brain or the blood vessels. The kidney is responsible for handling sodium and adjusting blood volume and is the site of action of diuretics, which enhance sodium excretion and lower blood pressure. The brain integrates afferent signals from peripheral sites such as the kidney and vasculature and sends efferent neural impulses to the heart and blood vessels. Finally, systemic vascular resistance is elevated in almost all adults with hypertension, suggesting that arteriolar vasoconstriction has an important role in this disease. The specific roles of these various organs and the way in which they work together to modulate blood pressure have been studied for more than a half century without satisfactory resolution.In the current issue of Nature Medicine, Titze and his colleagues1 identify another potential player in blood pressure regulationthe sub-cutaneous lymphatic system1. This system col-lects tissue fluid, proteins and cells from the interstitial extracellular space and transports them back into the circulation; the lymphatic system also plays a major part in immunologi-cal surveillance. The new findings suggest that, in addition to these traditional roles, lymph ves-sels under the skin can act as a fluid buffering system to blunt the blood pressure rise during excessive salt intake.For decades, a high-salt diet has been linked with elevated blood pressure in a subset of the population2,3; however, the precise under-standing of why excessive salt increases blood pressure remains elusive. When studying the effects of high salt intake on blood pressure, researchers often examine changes in the dis-tribution of sodium and water between the bodys intracellular and extracellular com-partments and how they relate to high blood pressure. This is commonly referred to in the majority of physiology textbooks as the two- compartment model. Several recent studies from Titzes group challenge this current dogma of a two-compartment model and propose that sodium (Na+) can be stored on proteoglycans in interstitial sites, where it becomes osmoti-cally inactive4,5. This uniquely bound Na+ can induce a state of local hypertertonicity in the skin interstitium. The precise mechanisms by which this bound Na+ can signal adjacent cells have been unclear.nature medicine volume 15 | number 5 | may 2009 487Kim CaesarEpidermisDermisSubcutaneous interstitiumNa+Na+Na+Na+Na+Na+ Na+Na+Na+Na+Na+LymphaticvesselsMacrophageVEGF-C Blood pressure TonEBP TonEBP TonEBPNormal salt High saltFigure 1 Increased subcutaneous Na+ modulates lymphangiogenesis and blood pressure. After high salt intake, osmotically inactive Na+ accumulates in the skin interstitium, binding proteoglycans. Macrophages accumulate in the subcutaneous compartment, and increased interstitial tonicity activates TonEBP. TonEBP transactivates the VEGFC gene and increases VEGF-C secretion by macrophages. This increases lymph capillary density and attenuates the blood pressure response to high salt.2009 Nature America, Inc. All rights reserved.n e w s a n d v i e w sIn the current study, Titze and his colleagues1 suggest that local hypertonicity is sensed by macrophages, which then produce the angio-genic protein vascular endothelial growth fac-tor-C (VEGF-C). VEGF-C stimulates lymphatic vessel growth, creating a third fluid compart-ment that buffers the increased body Na+ and volume and ameliorates the high blood pressure associated with excess salt intake (Fig. 1). In studies of cultured macrophages, the authors showed that increased osmotic stress activates a transcription factor known to be activated in response to osmotic stress, tonicity enhanced binding protein (TonEBP), which, in turn, induces VEGF-C expression1. The authors also showed that this pathway is important in regulating blood pressure1. If it was blocked in rats by macrophage depletion or inhibition of VEGF-C signaling, blood pressure elevation was exacerbated. Finally, the authors provide evidence that this pathway might be activated in humans by showing elevated circulating concentrations of VEGF-C in individuals with hypertension1. It is conceivable that defects in this pathway could result in redistribution of volume to the intravascular space, which could further elevate blood pressure.Additional studies of this third fluid com-partment are needed to further understand its impact on blood pressure regulation and vol-ume homeostasis. One open question is how osmotically inactive Na+, such as that bound to proteoglycans, can induce a hypertonic state that can be sensed by adjacent cells such as mac-rophages. In this regard, the cell culture studies in which macrophages were exposed to high Na+ concentrations in the medium might not reflect conditions in the in vivo subcutaneous intersti-tium, where the Na+ is not free but supposedly bound to proteoglycans and thus osmotically inactive. Estimates of the absolute volume and electrolyte content of this subcutaneous intersti-tial compartment, although difficult to obtain, would be informative. For example, it would be useful to understand how various hyperten-sive states and antihypertensive drugs affect the distribution of fluid between the subcutaneous lymphatic compartment and the intravascular space. It is quite possible that this subcutaneous interstitial space is affected differently by high blood pressure of different causes, such as that caused by kidney disease, renovascular hyper-tension, excessive catecholamines or essential hypertension. It is also possible that the subset of the population predisposed to salt-sensitive hypertension may have a dysfunctional Na+ buffering mechanism in the skin interstitium. The new findings might also explain why anti-angiogenesis drugs that block VEGF signaling, commonly used for the treatment of cancer, often cause hypertension6.Macrophages have a key role in innate immunity and are commonly viewed as evil doers in cardiovascular disease7,8. The cur-rent findings suggest that macrophages can be beneficial in modulating salt-sensitive hyper-tension and that treatment strategies to inhibit macrophage function might be deleterious in this setting. Recent studies have implicated cells of the adaptive immune system, in particular T cells, in the pathogenesis of hypertension9,10. These cells are transported by lymphatic ves-sels, and it is possible that they affect the ability of lymphatic vessels to modulate blood pres-sure. Moreover, there are crucial interactions between T cells and macrophages that could influence the ability of macrophages to par-ticipate in the pathway defined in the current study11.The findings presented by Titze and his col-leagues1 and other recent studies emphasize the complexity of blood pressure regulation. These studies indicate that uniquely stored sodium, the skin subcutaneous lymphatic vessels and macrophages contribute to volume homeostasis and blood pressure control. Future challenges will be developing tools and applications to study the interactions between the skin inter-stitium and other organs, such as the kidney, brain and the vasculature, that modulate blood pressure.1. Machnik, A. et al. Nat. Med. 15, 545552 (2009).2. Campese, V.M. Hypertension 23, 531550 (1994).3. Weinberger, M.H. Hypertension 27, 481490 (1996).4. Titze, J. et al. Am. J. Physiol. Renal Physiol. 285, F1108F1117 (2003).5. Schafflhuber, M. et al. Am. J. Physiol. Renal Physiol. 292, F1490F1500 (2007).6. Izzedine, H., et al. Ann. Oncol. published online, doi:10.1093/annonc/mdn713 (15 January 2009).7. Hansson, G.K. N. Engl. J. Med. 352, 16851695 (2005).8. Yan, Z.Q. & Hansson, G.K. Immunol. Rev. 219, 187203 (2007).9. Guzik, T.J. et al. J. Exp. Med. 204, 24492460 (2007).10. Crowley, S.D. et al. Am. J. Physiol. Renal Physiol. 295, F515F524 (2008).11. Monaco, C., Andreakos, E., Kiriakidis, S., Feldmann, M. & Paleolog, E. Curr. Drug Targets Inflamm. Allergy 3, 3542 (2004).488 volume 15 | number 5 | may 2009 nature medicineBreaking the gene barrier in schizophreniaSzatmr Horvth & Kroly MirnicsStudies of schizophrenia have been plagued by shortcomings such as weak genetic association with disease, inadequate animal models and limited replication of gene expression findings. Future success may lie not in overcoming any one of these limitations but in a broad approach strengthening the evidence in each area. Using such an approach, neuroscientists have uncovered a new gene behind the disease (pages 509518).Kroly Mirnics is in the Department of Psychiatry, Vanderbilt University, Nashville, Tennessee, USA. Szatmr Horvth is in the Department of Psychiatry, Vanderbilt University, Nashville, Tennessee, USA, and the Department of Psychiatry, University of Szeged, Szeged, Hungary. e-mail: karoly.mirnics@vanderbilt.eduWhat does it take to identify a gene that is crucial for the pathophysiology of schizo-phrenia? A genetic association replicated across several cohorts? Postmortem changes in the brains of diseased individuals? Gene effects on brain structure and cognitive pro-cessing? All of above, and some more. The study by Huffaker et al.1 in this issue of Nature Medicine has it all, providing com-pelling evidence that the KCNH2 gene, which encodes a membrane-spanning potassium channel, may be a strong contributor to the disease phenotype. Additionally, the authors show that KCNH2 has a role in cortical phys-iology, cognition and psychosis. Schizophrenia is a devastating brain dis-order characterized by abnormal mental functions and disturbed behavior2 (Fig. 1). Vulnerability to schizophrenia is clearly related to genetic factors. Yet, the inheritance of this complicated disease is nonmendelian, as alleles in multiple genes carry moderate to small effects in predisposing to the dis-ease3. The genetic and genome-wide asso-ciation studies in the last few decades have 2009 Nature America, Inc. All rights reserved.