High-Salt Diet Causes Expansion of the Lymphatic Network and Increased Lymph Flow in Skin and Muscle of Rats

Abstract

Objective— A commonly accepted pivotal mechanism in fluid volume and blood pressure regulation is the parallel relationship between body Na + and extracellular fluid content. Several recent studies have, however, shown that a considerable amount of Na + can be retained in skin without commensurate water retention. Here, we asked whether a salt accumulation shown to result in VEGF (vascular endothelial growth factor)-C secretion and lymphangiogenesis had any influence on lymphatic function. Approach and Results— By optical imaging of macromolecular tracer washout in skin, we found that salt accumulation resulted in an increase in lymph flow of 26% that was noticeable only after including an overnight recording period. Surprisingly, lymph flow in skeletal muscle recorded with a new positron emission tomography/computed tomography method was also increased after salt exposure. The transcapillary filtration was unaffected by the high-salt diet and deoxycorticosterone-salt treatment, suggesting that the capillary barrier was not influenced by the salt accumulation. A significant reduction in lymph flow after depletion of macrophages/monocytes by clodronate suggests these cells are involved in the observed lymph flow response, together with collecting vessels shown here to enhance their contraction frequency as a response to extracellular Na + . Conclusions— The observed changes in lymph flow suggest that the lymphatics may influence long-term regulation of tissue fluid balance during salt accumulation by contributing to fluid homeostasis in skin and muscle. Our studies identify lymph clearance as a potential disease-modifying factor that might be targeted in conditions characterized by salt accumulation like chronic kidney disease and salt-sensitive hypertension.

Salt-sensitive blood pressure rise in type 1 diabetes patients is accompanied by disturbed skin macrophage influx and lymphatic dilation—a proof-of-concept study

“…21 Macrophage depletion leads to a disturbance in the HSD-induced increase in lymphatic density 6 as well as lymphatic function. 18,22 In contrast to animal data, the lymphatic adaption in healthy controls in the present study did not involve an increased density (ie, number) but rather a dilation of existing lymphatic vessels. 6 This might be due to the relatively short (1-week) duration of the diet, which is shorter than the 9-day to 2-week diets in the animal studies (especially relative to life span), and may be too short for structural changes in lymphatics in humans.…”

“…17 How the lymphatic system influences BP is not fully uncovered. HSD-induced lymphatic changes are not only anatomic but also functional, as shown by increased lymphatic flow 18 and enhanced myogenic activity of isolated lymphatic vessels 19 in HSD-fed rats. Clearance of tissue water and electrolytes might play a role, enabling lowering of skin sodium content to preserve the availability for sodium storage and/or to preserve endothelial function (high sodium content was shown to increase vasoconstriction of blood vessels in rat models 20 ).…”

Tissue sodium excess is not hypertonic and reflects extracellular volume expansion

“…Response to 62. 5 Supplementary Table 1a, b) and SNP (endothelium-independent nitric oxide donor; n = 9-16/group, please see Supplementary Table 1a, b), respectively; mean ± SEM. Differences in maximal responses and half maximal effective/inhibitory concentrations (EC 50 and IC 50 , respectively) across groups are shown by brackets; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, at Extra sum-of-squares F test upon non-linear regression by least-square method.…”

“…In the last decade, the concept of tissue Na + shifted the traditionally nephrocentric view of Na + homoeostasis to the interstitium 1 , 2 , where the negatively charged glycosaminoglycans and a TonEBP/NFAT5-VEGF-c-mediated expansion of the lymphatic network serve as a depot and draining system for its accumulation, respectively 3 – 5 . The proposed water-independent nature of this phenomenon 6 – 8 marked its novelty 9 , 10 and its potential implications in the pathogenesis of hypertension and cardiovascular disease at large, as independent studies reported a boosted activation of pathogenic immune-inflammatory cells upon culture in supraphysiological concentrations of Na + 11 – 15 .…”

Acute body sodium depletion induces skin sodium mobilization in female Wistar rats

“…() reported that mobilization of osmotically inactive skin Na + could occur in order to maintain plasma Na + homeostasis and osmolality during chronic salt‐deprived conditions, whereas our study demonstrated that acute pharmacological Na + depletion can also induce mobilization of inactive skin Na + , in order to avoid severe forms of hyponatraemia. Previous studies have proposed that hypertonicity in the extracellular matrix recruits myeloid cells in the skin, increasing the expression of TonEBP (tonicity enhancing binding protein; Wiig et al., ), releasing skin sodium, which is then drained through lymph vessels (Karlsen et al., ).…”