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We recently reported that skin vasoconstriction to suppress transepidermal water loss (TEWL) leads to hypertension in renal injury model rats with impaired urine concentration ability. In this study, we investigated the pathogenesis of hypertension in spontaneously hypertensive rats (SHRs) from the perspective of renal water loss and skin water conservation. We compared the urinary concentration ability, body sodium and water balance, blood pressure, and TEWL in SHRs and control normotensive Wistar-Kyoto rats (WKYs). SHRs showed significantly higher urine volume and lower urinary osmolality than those of WKYs, while there were no significant differences in water intake, urinary osmolyte excretion, and plasma osmolarity between the groups. SHRs exhibited significantly higher blood pressure, skin sodium content, and lower TEWL compared with those is WKYs. Skin vasodilation, induced by elevating body temperature, increased TEWL in both SHRs and WKYs, and significantly reduced blood pressure in SHRs but not WKYs. These findings suggest that physiological adaptation can reduce dermal water loss in SHRs to compensate for renal water loss. Vasoconstriction required for successful cutaneous water conservation explains SHR hypertension. Renal concentration ability and skin barrier function for water conservation may become a novel therapeutic target for essential hypertension.

Therapeutic inhibition of the sodium–glucose co-transporter 2 (SGLT2) leads to substantial loss of energy (in the form of glucose) and additional solutes (in the form of Na+ and its accompanying anions) in urine. However, despite the continuously elevated solute excretion, long-term osmotic diuresis does not occur in humans with SGLT2 inhibition. Rather, patients on SGLT2 inhibitor therapy adjust to the reduction in energy availability and conserve water. The metabolic adaptations that are induced by SGLT2 inhibition are similar to those observed in aestivation — an evolutionarily conserved survival strategy that enables physiological adaptation to energy and water shortage. Aestivators exploit amino acids from muscle to produce glucose and fatty acid fuels. This endogenous energy supply chain is coupled with nitrogen transfer for organic osmolyte production, which allows parallel water conservation. Moreover, this process is often accompanied by a reduction in metabolic rate. By comparing aestivation metabolism with the fuel switches that occur during therapeutic SGLT2 inhibition, we suggest that SGLT2 inhibitors induce aestivation-like metabolic patterns, which may contribute to the improvements in cardiac and renal function observed with this class of therapeutics. SGLT2 inhibitors induce a number of metabolic adaptations in response to increased glucose and Na+ excretion. This Perspective article describes how these adaptations suggest that SGLT2 inhibition triggers a body water-conserving mechanism, and discusses how these metabolic adjustments may contribute to the favourable cardiovascular and renal outcomes of this class of therapeutics.

We recently reported that a 4% high-salt diet + saline for drinking (HS + saline) leads to a catabolic state, reduced heart rate, and suppression of cardiovascular energy expenditure in mice. We suggested that HS + saline reduces heart rate via the suppression of the sympathetic nervous system to compensate for the high salt intake-induced catabolic state. To test this hypothesis, we directly measured renal sympathetic nerve activity (RSNA) in conscious Sprague-Dawley (SD) rats using a radiotelemetry system. We confirmed that HS + saline induced a catabolic state. HS + saline decreased heart rate, while also reducing RSNA in SD rats. In contrast, Dahl salt-sensitive (DSS) rats exhibited no change in heart rate and increased RSNA during high salt intake. Renal denervation significantly decreased heart rate and attenuated the catabolic state independent of blood pressure in DSS rats fed HS + saline, suggesting that salt-sensitive animals were unable to decrease cardiovascular energy consumption due to abnormal renal sympathetic nerve activation during high salt intake. These findings support the hypothesis that RSNA mediates heart rate during high salt intake in SD rats. However, the insensitivity of heart rate and enhanced RSNA observed in DSS rats may be additional critical diagnostic factors for salt-sensitive hypertension. Renal denervation may benefit salt-sensitive hypertension by reducing its effects on catabolism and cardiovascular energy expenditure.

Renal denervation (RDN) has been introduced for reducing blood pressure (BP) in treatment-resistant hypertension (TRH). The precise mechanism how RDN exerts its BP-lowering effects are not yet fully understood. It is widely accepted that sodium (Na+) plays a crucial role in the pathogenesis of hypertensive disease. However, there is increasing evidence of osmotically inactive Na+ storage. We investigated the impact of RDN on Na+ homeostasis using estimation of salt intake, and measurement of tissue Na+ content. In a study 41 patients with TRH (office BP ≥140/90 mmHg and diagnosis confirmed by 24-h ambulatory BP monitoring) underwent RDN. Tissue Na+ content was assessed non-invasively with 3.0 T magnetic resonance imaging before and 6 months after RDN. In addition, 24-h urinary Na+ excretion as an estimate of salt intake and spot urine Na+/K+ excretion were assessed. The study was registered at http://www.clinicaltrials.gov (ID: NCT01687725). There was a significant fall in BP (office: −17 ± 20/−10 ± 12 mmHg; 24-h: −11 ± 13/−6 ± 9 mmHg, all p

Purpose 23Na MRI demonstrated increased tissue sodium concentrations in a number of pathologies. Acute atrophy results in muscle fibre volume shrinking that may result in a relative increase of extracellular volume and might affect sodium concentration. Thus, we hypothesized that local unloading of the calf muscles would lead to a decrease in muscle volume and an increase in muscle tissue sodium concentration. Method One lower leg of 12 healthy male subjects was submitted to a 60 day long period of unloading using the Hephaistos orthosis, while the other leg served as control. 23Na MRI and 2D PD-weighted Dixon turbo spin echo were obtained from the control and orthosis leg using a 3T scanner. For quantification, a sodium reference phantom was used with 10, 20, 30, and 40 mmol/L NaCl solution. Result Tissue sodium concentration (TSC) increased as an effect of unloading in the orthosis leg. Relative increases were 17.4 ± 16.8% (P = 0.005) in gastrocnemius medialis muscle, 11.1 ± 12.5 (P = 0.037) in gastrocnemius lateralis muscle, 16.2 ± 4.7% (P < 0.001) in soleus muscle, 10.0 ± 10.5% (P = 0.009) in the ventral muscle group, and 10.7 ± 10.0% (P = 0.003) in the central muscle group, respectively. TSC in the control leg did not significantly change. In the orthosis leg, muscle volume decreased as follows: medial gastrocnemius muscle: −5.4 ± 8.3% (P = 0.043) and soleus muscle: −7.8 ± 15.0% (P = 0.043). Conclusion Unloading atrophy is associated with an increase in muscle sodium concentration. 23Na MRI is capable of detecting these rather small changes.

Recent evidence from chemical analysis of tissue electrolyte and water composition has shown that body Na(+) content in experimental animals is not constant, does not always readily equilibrate with water, and cannot be exclusively controlled by the renal blood purification process. Instead, large amounts of Na(+) are stored in the skin and in skeletal muscle. Quantitative non-invasive detection of Na(+) reservoirs with sodium magnetic resonance imaging ((23)NaMRI) suggests that this mysterious Na(+) storage is not only an animal research curiosity but also exists in humans. In clinical studies, tissue Na(+) storage is closely associated with essential hypertension. In animal experiments, modulation of reservoir tissue Na(+) content leads to predictable blood pressure changes. The available evidence thus suggests that the patho(?)-physiological process of Na(+) storage might be of relevance for human health and disease.

There has been a marked increase in the incidence of autoimmune diseases in the past half-century. Although the underlying genetic basis of this class of diseases has recently been elucidated, implicating predominantly immune-response genes, changes in environmental factors must ultimately be driving this increase. The newly identified population of interleukin (IL)-17-producing CD4(+) helper T cells (TH17 cells) has a pivotal role in autoimmune diseases. Pathogenic IL-23-dependent TH17 cells have been shown to be critical for the development of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, and genetic risk factors associated with multiple sclerosis are related to the IL-23-TH17 pathway. However, little is known about the environmental factors that directly influence TH17 cells. Here we show that increased salt (sodium chloride, NaCl) concentrations found locally under physiological conditions in vivo markedly boost the induction of murine and human TH17 cells. High-salt conditions activate the p38/MAPK pathway involving nuclear factor of activated T cells 5 (NFAT5; also called TONEBP) and serum/glucocorticoid-regulated kinase 1 (SGK1) during cytokine-induced TH17 polarization. Gene silencing or chemical inhibition of p38/MAPK, NFAT5 or SGK1 abrogates the high-salt-induced TH17 cell development. The TH17 cells generated under high-salt conditions display a highly pathogenic and stable phenotype characterized by the upregulation of the pro-inflammatory cytokines GM-CSF, TNF-α and IL-2. Moreover, mice fed with a high-salt diet develop a more severe form of EAE, in line with augmented central nervous system infiltrating and peripherally induced antigen-specific TH17 cells. Thus, increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic TH17 cells.

According to the generally accepted view, sodium accumulation in the human body takes place in the extracellular space and is accompanied by an increase in the rate of fluid retention and body weight gain. However, this view was revised in recent studies, which demonstrated that sodium could be accumulated in the human body without expansion of the extracellular space. Sodium exchange and its effect on body weight (BW) were investigated in long-term balance studies. Three apparently healthy volunteer subjects were confined for 135 days to a ground-based model of the main unit of the Mir space station, where they were exposed to model conditions similar to conditions of actual long-term spaceflight. The daily balance of sodium and its contribution to BW changes were studied. During the period of observation, the subjects accumulated 2.973–7.324 mmol of sodium and gained 5.1–9.3 kg. Initially, there was a positive correlation between changes in the total body sodium and the BW, which reflected sodium-dependent extracellular space expansion. However, by the end of the period of isolation, the relative rate of body weight gain was lower than the relative rate of gain in the total body sodium, which suggested that sodium accumulated in an osmotically inactive form. The fact that sodium accumulated without BW gain suggests that isolation of healthy subjects in a hermetically sealed enclosure stimulates sodium accumulation in the body in an osmotically inactive form. The sodium-storing processes activated under these conditions might be localized in bone, connective tissue (skin), or cartilage. Rhythmic variation in the net sodium balance was observed and attributed to oscillations of renal excretion of aldosterone. It is obvious that the depot of osmotically inactive sodium should be taken into account in studies of cardiovascular system function and in pathophysiological approaches to edematous syndrome and hypertension.