New Approaches to Pathogenesis and Management of Hypertension (2009)

A classical concept about the relationship between salt (NaCl) and extracellular volume was that salt was retained as an isosmotic fluid and that equilibration between sodium intake and output was achieved after approximately 5 d (1). This view has become problematic after disquieting deviations from the prediction were found in astronauts who went into substantially positive sodium balance without gaining weight, apparently storing salt without expanding the extracellular fluid space (2,3). This unexpected violation of past paradigms found an explanation in the observation of Titze et al. (4) that sodium, in addition to or instead of expanding the extracellular fluid space, may undergo ionic interaction with negatively charged glycosaminoglycans (GAG) of the skin by binding directly as a cation to the polysulfated negatively charged GAG GAG. This has important implications for salt-induced changes in body weight, tissue hydration, and BP regulation (5). These novel findings concerning the mechanism of sodium retention without commensurate weight gain are irreconcilable with the classical concept that sodium is retained primarily or exclusively by isosmotic expansion of the extracellular fluid. Salt does not only cause edema and hypertension but also BP-independent target organ damage (e.g., of heart and kidney) (6–8). The article discussed here now goes one step further and documents that salt not only can be stored nonosmotically (i.e., without expanding the extracellular fluid) but also can trigger lymphangiogenesis in the skin. A number of past experimental studies had documented that salt loading caused BP-independent organ damage and inflammation (6,9,10). This issue of BP-independent effects of salt has been given a new twist by this study by Machnik et al.: The authors amplified past observations of nonosmotic storage sodium in the skin and documented added complexity. They now show that storage of salt in the skin triggers lymphangiogenesis by a complicated sequence of events and thus further impacts on BP. The pointer in this direction was recent observations that macrophages (i.e., the mononuclear phagocyte system) influence lymphangiogenesis and that, in a malignancy model, hypertonicity macrophage–produced factors triggered peritumoral lymph vessels (11,12). Furthermore, osmotic stress had been defined as a critical feature of the lymphoid microenvironment (13). The authors tied all of these suggestions together and documented that hypertonicity of the interstitium as produced by feeding a high-salt diet provoked macrophage signaling, resulting in the secretion of an isoform of vascular endothelial growth factor (VEGF), VEGF-C, a known factor that promotes lymphangiogenesis. The authors found stimulation of lymphangiogenesis in mice fed a high-salt compared with a low-salt diet as documented by three-dimensional reconstruction of the lymph system. The causal role of macrophages for lymphangiogenesis was proved by the experiment that selective deletion of macrophages by clodronate-containing liposomes prevented lymphangiogenesis: Clodronate-containing liposomes are taken up by macrophages but are toxic for them. Elimination of macrophages by clodronate-containing liposomes caused greater expansion of the extracellular space and higher BP values. These observations raised the issue of which signal is responsible for lymphangiogenesis. Promotion of lymphangiogenesis by macrophages was dependent on a molecule that has been known to immunologists for quite some time as tonicity-responsive enhancer–binding protein (TonEBP) (13). Incubation of macrophages at high as compared with low NaCl concentrations increased the expression of TonEBP on the mRNA and protein level. TonEBP binds the promoter of the gene encoding VEGF-C, causing VEGF-C secretion by macrophages. The causal role of VEGF-C secretion by macrophages was proved by depleting or trapping VEGF by soluble VEGF-C receptor 3: Blocking VEGF-C signaling augmented interstitial hypertonic volume retention and decreased endothelial nitric oxide synthase (eNOS) expression, causing major BP elevation in response to high-salt diet. So VEGF-C has been identified as the osmosensitive hypertonicity-driven gene involved in the genesis of salt-induced hypertension. The issue that arises is whether this Na+ overload–triggered macrophage response via TonEBP and VEGF-C is injurious or is beneficial by counteracting the effect of high salt. The authors showed that VEGF-C binds not only to the VEGF receptor (VEGFR3) of lymphatic vessels but also to the endothelial VEGFR2 receptor, activation of which upregulates the production of vasodilatory NO. In other words, sodium overload, which tends to raise BP, also causes compensatory production of vasodilatory NO, which counteracts the pressure-inducing effect of salt. The efficacy of this compensatory mechanism is illustrated by the observation that eNOS knockout animals develop more severe hypertension upon salt loading (14). The sequence of events can be summarized as shown here: Na load → interstitial Na+ ↑ → TonEBP activated → VEGF-C ↑ → lymphangiogenesis → drainage → endothelial cell eNOS↑ → vasodilation The human relevance of this pathway is illustrated by the finding that in 25 patients with refractory hypertension—as compared with 15 control individuals—the plasma VEGF-C concentrations were significantly higher. This study adds one further potential mechanism to the genesis of high BP. The ramifications for hypertension in chronic kidney disease are difficult to predict. It is an expression of the intelligence of nature that salt loading automatically increases NO synthesis by endothelial cells to limit salt-induced increase in BP, but the question that has to be addressed is whether this compensatory mechanism is disturbed in renal failure and whether this is relevant for the particular salt sensitivity of patients with chronic kidney disease. The storage of sodium without a commensurate increase in water must certainly caution against equating sodium retention with weight gain in dialysis patients; the aforementioned mechanism would allow for sodium retention in the absence of weight gain—similar to what has been observed in astronauts (2). This has implications for the dry weight, which had originally been defined as the “body weight in the normotensive, nonedematous patient on dialysis”—the rationale to rely on weight alone deserves to be rethought. The storage of sodium may also be relevant to understanding the lag phenomenon (i.e., the delayed decrease of BP in response to reduction of extracellular volume) (15,16). Potentially prolonged elevation of BP may reflect the delayed release of sodium certainly not strictly related to the size of the extracellular space. In retrospect, one can only admire the clinical acumen of Scribner et al. (17), who wrote in 1960, “As in the case of nephrectomized dogs, hypertension appears to be influenced by the size of the extracellular space. The combination of dietary sodium restriction and ultrafiltration during dialysis permits regulation of extracellular volume—although the explanation may no longer be perfectly correct, the practical consequences certainly are.”