Salty Skin: Where Excess Sodium Goes for a Rendezvous

Cardiovascular diseases (CVDs) are the leading cause of global mortality and include clinical conditions such as hypertension and heart failure (HF). While several genetic, social, and lifestyle factors likely contribute to the pathogenesis of CVD, chronic excessive salt, specifically sodium, consumption is a major risk factor. To counteract excess sodium consumption, the kidneys regulate sodium balance by altering sodium retention and excretion to maintain cardiovascular homeostasis [1]. Renal excretion of excess sodium involves several redundant mechanistic pathways, including arterial pressure, renal sympathetic tone, the renin-angiotensin-aldosterone system, and atrial natriuretic peptide, which work in concert to adjust glomerular filtration rate and total tubular reabsorption. Recently, the contribution from extra-renal mechanisms (i.e., skin, muscle, bone, connective tissues, etc.) has become increasingly recognized as a pivotal regulator of sodium balance and may ultimately play an important role in blood pressure regulation and CVD pathogenesis.

Of particular interest is the recent study by Thowsen et al. in the Journal of Physiology [2], which sought to investigate the role skin may play as an extra-renal mechanism in regulating blood pressure via sodium accumulation during high-salt conditions. Specifically, the skin interstitium may act as a reservoir to store osmotically inactive sodium without affecting water retention. This may be, in part, due to the skin interstitium’s high content of sulphated glycosaminoglycans (sGAGs), which are large negatively charged disaccharide chains. Thowsen et al. [2] tested the hypotheses that a sodium gradient in the skin was present with an increasing content towards the surface due to a counter current mechanism and that sGAGs may be responsible for the osmotically inactive sodium accumulation. In this study, male Sprague-Dawley rats (11–15 weeks old) underwent either a high-salt diet (HSD) or deoxycorticosterone acetate (DOCA)-salt pellet implantation; rats on a low-salt diet (LSD) served as a control group. HSD rats consumed 8% NaCl in their chow and drank 1% saline, DOCA-salt rats drank 1% saline, and LSD rats consumed <0.1% NaCl chow and drank tap water. After two weeks, rats were sacrificed and dissected for skin and muscle tissues. Skin samples were used to investigate electrolyte concentrations, components of intracellular and extracellular matrices at various depths of the skin, and determine the presence of microscopic vascular loops [2]. Skeletal and cardiac muscle tissues were used to determine intracellular (ICV), extracellular (ECV), and interstitial fluid volumes [2].

Compared to LSD, sodium concentration, expressed in both dry and wet weights, increased in the whole skin and dermis, but not the epidermis, in both HSD and DOCA-salt groups. However, water content in the whole skin and dermis increased only in the HSD group [2]. The findings of a selective accumulation of sodium in the deeper layer (i.e., dermis) of the skin during high-salt conditions suggest that sodium deposit in the skin is highly compartmentalized. While excess sodium can be stored intra- and extracellularly, their additional findings of no change in sodium content in the skin interstitial fluid suggests the intracellular fluid compartment as a predominant sodium storage site [2]. Furthermore, compared to LSD, sGAG concentration in the whole skin and dermis did not change in the HSD group and was lower in the DOCA group, suggesting that sGAGs were unaffected by high-salt conditions in this study [2]. Importantly, despite a selective accumulation of sodium in the dermis, as opposed to a more superficial skin layer (i.e., epidermis), the lack of superficial vascular loops in the dermis opposed the hypothesis of a counter-current mechanism in the skin [2]. Collectively, these findings have identified the dermis as a selective area of skin sodium accumulation from diets high in sodium and identified that there may be additional mechanisms, besides sGAGs, that are responsible for skin sodium accumulation.

In the ICV of both the skeletal and cardiac muscles, sodium concentrations were increased in HSD and DOCA groups. Potassium concentrations increased in the cardiac muscle ICV of the HSD group and decreased in the skeletal muscle ICV of the DOCA group [2]. Relative to the LSD group, extracellular sodium concentration in skeletal and cardiac muscle tissue was increased in both HSD and DOCA groups [2]. Despite increases in the sodium concentrations, only the DOCA group had an increase in ECV compared to the LSD group. Cumulative sodium and potassium concentrations relative to water in the ECV of skeletal and cardiac muscles did not differ between groups [2]. Compared to the LSD group, sodium concentration increased and potassium concentrations decreased in the skeletal muscle interstitial fluid in the DOCA group, but not in the HSD group [2]. Taken together, these findings have identified skeletal and cardiac muscles as additional sodium storage sites and also highlight the differential control of fluid volume and electrolyte balance (i.e., exchanging sodium and potassium) in different fluid compartments of both skeletal and cardiac muscles that warrants further investigation.

Though Thowsen et al. [2] provided important insight into various compartments (i.e., skin, skeletal muscle, and cardiac muscle) by which excess sodium can be stored during high-salt conditions, several questions remain regarding mechanistic underpinnings and physiological consequences of sodium accumulation in the skin and other extrarenal tissues. Indeed, Wenstedt et al. [3] recently evaluated the influence of short-term (2 weeks) LSD (<3 g NaCI per day) versus HSD (>12 g NaCl per day) on pro-inflammatory responses in healthy, young human adults. Specifically, HSD resulted in elevations in systolic blood pressure that were accompanied by increases in plasma monocyte chemoattractant protein-1, transendothelial migration of monocytes, skin macrophage density, and expression of the monocyte migration marker, CCR2 [3]. These findings [3], taken together with the data from Thowsen et al. [2], suggest a potential immunologic mechanism that may further explain the role of sodium in the pathogenesis of CVD. However, whether excess sodium-induced pro-inflammatory responses may play a role in sGAG expression deserves further investigation.

Another mechanism by which excess sodium intake contributes to the pathogenesis of CVD may be related, in part, to a reduction in nitric oxide (NO) bioavailability and, thus, endothelial dysfunction [4]. Specifically, excess sodium intake can induce cellular oxidative stress via activation of nicotinamide adenine dinucleotide phosphate oxidase while inhibiting anti-oxidant mechanisms (i.e., superoxide dismutase isoforms), thereby increasing the presence of reactive oxygen species (ROS) [4]. For example, superoxide scavenges NO, reducing its bioavailability while increasing formation of the extremely potent ROS, peroxynitrite [4]. Furthermore, peroxynitrite can, in turn, oxidize tetrahydrobiopterin, an essential co-factor of NO synthase, effectively uncoupling the main NO-producing enzyme, thereby reducing NO production and further promoting increases in cellular oxidative stress [4]. As a result, pathological processes such as endothelial dysfunction and endothelial cell stiffness, may ensue and promote pro-atherosclerotic conditions [4]. Given that excess sodium consumption may induce endothelial dysfunction, which is a well-recognized contributor in the pathogenesis of CVD, it is possible that sequestering sodium from the blood into the skin interstitium may be an early effort by the body to maintain cardiovascular homeostasis in the presence of excessive sodium consumption. Conversely, the long-term effects of unresolved hypernatremic skin interstitial environments have been associated with the pathogenesis of cardiovascular disease [5].

The findings from Thowsen et al. [2] have clinical relevance, as excessive sodium consumption is associated with the pathogenesis of CVD, including HF. In a recent exploratory analysis, Lemoine et al. [5] sought to examine skin sodium content in patients with HF with a reduced ejection fraction and patients with chronic kidney disease (CKD) and observed greater skin sodium content in patients with HF compared to patients with CKD despite being matched for glomerular filtration rate. In parallel with the findings of increased sodium deposition into the cardiac and skeletal muscles of rats in the study by Thowsen et al. [2], patients with HF also exhibited higher sodium content within the calf muscle compared to patients with CKD, suggesting that sodium can be stored in both skin and muscle tissues in humans. Though skin sodium content was assessed via ²³Na-magnetic resonance imaging of the calf of these patients [5], these data, considered together with the findings by Thowsen et al. [2], highlight the importance of assessing dermal and muscular sodium concentrations as a potential, quantifiable, risk factor for the development and progression of CVD.

In conclusion, Thowsen et al. [2] have provided novel and insightful data that offer groundwork for subsequent mechanistic and clinical studies to further explore the health consequences of skin and tissue sodium accumulation in humans. These findings are of particular interest to our respective research groups given their potential insights into the vascular and immunological mechanisms associated with high dietary sodium. Future studies should consider evaluating mechanisms and physiological consequences of excess sodium accumulation in the skin and muscle tissues on vascular health in health and disease, translating findings from animal models to human participants. In conjunction with the suggestion by Thowsen et al. [2] regarding the interaction between inflammation and sGAGs, further investigation into the impact of high sodium on individual immune cells is also warranted.

Abbreviations:

CKD

chronic kidney disease

CVD

cardiovascular disease

DOCA

deoxycorticosterone acetate

ECV

extracellular fluid volume

HF

heart failure

HSD

high-salt diet

ICV

intracellular fluid volume

LSD

low-salt diet

NO

nitric oxide

ROS

reactive oxygen species

sGAGs

sulphated glycosaminoglycans