Sodium Balance Research Articles

Proteolytic Activation of the Epithelial Sodium Channel (ENaC): Its Mechanisms and Implications.

Epithelial sodium channel (ENaC) are integral to maintaining salt and water homeostasis in various biological tissues, including the kidney, lung, and colon. They enable the selective reabsorption of sodium ions, which is a process critical for controlling blood pressure, electrolyte balance, and overall fluid volume. ENaC activity is finely controlled through proteolytic activation, a process wherein specific enzymes, or proteases, cleave ENaC subunits, resulting in channel activation and increased sodium reabsorption. This regulatory mechanism plays a pivotal role in adapting sodium transport to different physiological conditions. In this review article, we provide an in-depth exploration of the role of proteolytic activation in regulating ENaC activity. We elucidate the involvement of various proteases, including furin-like convertases, cysteine, and serine proteases, and detail the precise cleavage sites and regulatory mechanisms underlying ENaC activation by these proteases. We also discuss the physiological implications of proteolytic ENaC activation, focusing on its involvement in blood pressure regulation, pulmonary function, and intestinal sodium absorption. Understanding the mechanisms and consequences of ENaC proteolytic activation provides valuable insights into the pathophysiology of various diseases, including hypertension, pulmonary disorders, and various gastrointestinal conditions. Moreover, we discuss the potential therapeutic avenues that emerge from understanding these mechanisms, offering new possibilities for managing diseases associated with ENaC dysfunction. In summary, this review provides a comprehensive discussion of the intricate interplay between proteases and ENaC, emphasizing the significance of proteolytic activation in maintaining sodium and fluid balance in both health and disease.

Tangram of Sodium and Fluid Balance.

Homeostasis of fluid and electrolytes is a tightly controlled physiological process. Failure of this process is a hallmark of hypertension, chronic kidney disease, heart failure, and other acute and chronic diseases. While the kidney remains the major player in the control of whole-body fluid and electrolyte homeostasis, recent discoveries point toward more peripheral mechanisms leading to sodium storage in tissues, such as skin and muscle, and a link between this sodium and a range of diseases, including the conditions above. In this review, we describe multiple facets of sodium and fluid balance from traditional concepts to novel discoveries. We examine the differences between acute disruption of sodium balance and the longer term adaptation in chronic disease, highlighting areas that cannot be explained by a kidney-centric model alone. The theoretical and methodological challenges of more recently proposed models are discussed. We acknowledge the different roles of extracellular and intracellular spaces and propose an integrated model that maintains fluid and electrolyte homeostasis and can be distilled into a few elemental players: the microvasculature, the interstitium, and tissue cells. Understanding their interplay will guide a more precise treatment of conditions characterized by sodium excess, for which primary aldosteronism is presented as a prototype.

Fisetin Treats Kidney Oxidative Stress, Inflammation, and Apoptosis in Rat Diarrhea.

Diarrhea is the increase in the excretion of human water; meanwhile, fisetin, a bioactive flavonol molecule, is widely used in the treatment/prevention of gastrointestinal disorders. The purpose of this study is to investigate the anti-diarrheal activity of fisetin by restoring kidney function, antioxidant activity, inflammatory markers, Na+/K+-ATPase level, apoptosis, and protein content in diarrheal rats. A total of 36 male rats were distributed into two groups (18 rats/group): normal and diarrheal. The normal group was further divided into three subgroups (6 rats/subgroup): Control, fisetin, and desmopressin drug subgroups, consisting of normal rats orally treated once a day for 4 weeks with 1 mL distilled water, 50 mg/kg fisetin, and 1 mg/kg desmopressin drug, respectively. A lactose diet containing 35% lactose was fed to the normal rats for a month. The diarrheal rats were also divided into three subgroups (6 rats/subgroup): diarrheal rats, diarrheal rats + fisetin, and diarrheal rats + desmopressin drug groups, whereby the diarrheal rats were orally treated once a day for 4 weeks with 1 mL distilled water, 50 mg/kg fisetin, and 1 mg/kg desmopressin drug, respectively. Fisetin significantly decreased serum urea (41.20 ± 2.6-29.74 ± 2.65), creatinine (1.43 ± 0.05-0.79 ± 0.06), and urinary volume (1.30 ± 0.41-0.98 ± 0.20), while significantly increasing kidney weight (0.48 ± 0.03-0.67 ± 0.07), sodium, potassium, and chloride balance in both serum and urine. Fisetin significantly increased the antioxidant activity (superoxide dismutase (1170 ± 40-3230 ± 50), glutathione peroxidase (365 ± 18-775 ± 16), catalase (0.09 ± 0.03-0.14 ± 0.06), and nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase activity (8.6 ± 1.31-10.5 ± 1.25), while significantly decreasing malondialdehyde (19.38 ± 0.54-9.54 ± 0.83), conjugated dienes (1.86 ± 0.24-1.64 ± 0.19), and oxidative index (0.62 ± 0.04-0.54 ± 0.05)), alongside the inflammatory markers (tumor necrosis factor-α (65.2 ± 2.59-45.3 ± 2.64), interleukin-1β, interleukin-6 (107 ± 4.5-56.1 ± 7.2), and interleukin-10) in the diarrheal rats to values approaching the control values. Fisetin also restored the Na+/K+-ATPase level, apoptosis, protein content, and kidney architecture in diarrheal rats to be near the control group. Fisetin treated diarrhea in rats by restoring kidney function, antioxidant activity, inflammatory markers, apoptosis, proteome content, and histology.

An Exploration of Dietary Strategies for Hypertension Management: A Narrative Review.

This review aims to clarify the influence of various nutritional approaches in the management of hypertension.An extensive search of databases, namely, PubMed, Cochrane Library, Scopus, and Web of Science, was performed, covering the period from January 2012 to October 2023. We used keywords, such as "hypertension,""nutrition,""nutritional management,""nutrient intake,""dietary strategies,""DASH diet,""Mediterranean diet,"and related terms.Hypertension, a grave global health concern, affects more than one billion people worldwide. Lifestyle modifications, including nutritional strategies, are important in non-pharmacological interventions. Dietary patterns, such as the DASH (DietaryApproaches to Stop Hypertension) and Mediterranean diets, which emphasize fruit and vegetable consumption, have demonstrated efficacy in reducing blood pressure. Certain nutrients, such as potassium, calcium, and magnesium, have significant effects on blood pressure. The mechanisms underlying these dietary strategies include vasodilation, improvement in endothelial function, regulation of sodium balance, and mitigation of oxidative stress. However, successful implementation of these strategies can be hindered by various factors, such as adherence challenges, socioeconomic disparities, and cultural preferences. In conclusion, robust evidence supports the effectiveness of nutritional strategies in the management of hypertension. DASH and Mediterranean diets, along with an increased intake of specific nutrients, contribute to blood pressure reduction. Hence, comprehensive lifestyle modifications, with a focus on nutritional changes, are recommended as primary or complementary treatments for hypertension. Addressing the identified barriers could enhance the efficacy and use of these dietary approaches in clinical practice.

The role of intra- and interdialytic sodium balance and restriction in dialysis therapies.

The relationship between sodium, blood pressure and extracellular volume could not be more pronounced or complex than in a dialysis patient. We review the patients' sources of sodium exposure in the form of dietary salt intake, medication administration, and the dialysis treatment itself. In addition, the roles dialysis modalities, hemodialysis types, and dialysis fluid sodium concentration have on blood pressure, intradialytic symptoms, and interdialytic weight gain affect patient outcomes are discussed. We review whether sodium restriction (reduced salt intake), alteration in dialysis fluid sodium concentration and the different dialysis types have any impact on blood pressure, intradialytic symptoms, and interdialytic weight gain.

Association between urinary oxytocin secretion and natriuresis after transsphenoidal pituitary surgery.

Oxytocin (OXT) secretion has been shown to be abnormally elevated in patients who develop syndrome of inappropriate secretion of antidiuretic hormone (SIADH)-related hyponatremia after transsphenoidal pituitary surgery (TPS). While OXT was previously reported to increase natriuresis in the kidney, a potential role for this hormone in postoperative sodium balance and dysnatremias has not been studied. The objective of this study was to analyze the correlation between patients' urinary output of OXT and natremia and natriuresis after TPS. The authors measured and correlated the urinary output of OXT with natriuresis and natremia in 20 consecutive patients who underwent TPS. The ratio of urinary secretion of OXT between days 1 and 4 showed a strong, significant correlation with patient natriuresis at day 7 after pituitary surgery. Concomitantly, patient natremia showed a moderate, inverted correlation with OXT secretion in the urine. Together, these results show for the first time that urinary OXT secretion correlates with patient natriuresis and natremia after pituitary surgery. This observation suggests a notable role for this hormone in sodium balance.

Herbal medicine (Oryeongsan) for fluid and sodium balance in renal cortex of spontaneously hypertensive rats

BackgroundHerbal medicine Oryeongsan (ORS), also known as Wulingsan in Chinese, has been used for the treatment of impaired body fluid balance. However, the mechanisms involved are not clearly defined. The purpose of the present study was to identify the actions of ORS on the renal excretory function and blood pressure (BP) and to define the mechanisms involved in association with renin-angiotensin system (RAS) and natriuretic peptide system (NPS) in spontaneously hypertensive rats (SHR), an animal model of human essential hypertension. MethodsChanges in urine volume (UV), excretion of electrolytes including Na+ (urinary excretion of Na+ (UNaV)) were measured. RT-PCR was performed to trace the changes in expression of RAS, NPS and sodium (Na+)-hydrogen (H+) exchanger 3 (NHE3) in the renal cortex. ResultsIn the SHR treated with vehicle (SHR-V) group, UV and UNaV were suppressed and the Na+ balance was maintained at the higher levels leading to an increase in BP compared to WKY-V group. These were accompanied by an increase in NHE3 expression with an accentuation of angiotensin I converting enzyme-angiotensin II type 1 (ACE-AT1) receptor and concurrent suppression of angiotensin II type 2 (AT2) receptor/ACE2-Mas receptor expression in the renal cortex. Chronic treatment with ORS increased UV and UNaV, and decreased the Na+ and water balance with a decrease in BP in the ORS-treated SHR-ORS group compared to SHR-V. These were accompanied by a decrease in NHE3 expression with a suppression of ACE-AT1 receptor and concurrent accentuation of AT2/ACE2-Mas receptor. ConclusionThe present study shows that ORS reduced BP with a decrease in Na+ and water retention by a suppression of NHE3 expression via modulation of RAS and NPS in SHR. The present study provides pharmacological rationale for the treatment of hypertension with ORS in SHR.

Shikimic acid recovers diarrhea and its complications in SD rats fed lactose diet to induce diarrhea

BackgroundDiarrhea is the increase of excretion of human water content and an imbalance in the physiologic processes of the small and large intestine while shikimic acid is an important biochemical metabolite in plants. This study aims to study the anti-diarrheal activity of shikimic acid through restoring kidney function, antioxidant activity, inflammatory markers, sodium/potassium-ATPase activity, apoptosis genes, and histology of the kidney in SD rats fed lactose diet to induce diarrhea.ResultsThirty-six male SD rats (150 ± 10 g, 12 weeks old) were divided into 2 equal groups (18 rats/group) as follows: normal and diarrheal rats. Normal rats were divided into 3 equal groups of 6 rats each: the control, shikimic acid, and desmopressin drug groups. Diarrheal rats were also divided into 3 equal groups of 6 rats each: diarrheal, diarrheal rats + shikimic acid, and diarrheal rats + desmopressin drug groups. Shikimic acid restored serum urea and creatinine, urinary volume, kidney weight, sodium, potassium, and chloride balance in serum and urine. The acid returned the antioxidant (superoxide dismutase, glutathione peroxidase, catalase, malondialdehyde, NADPH oxidase activity, conjugated dienes, and oxidative index) activity and the inflammatory markers (tumor necrosis factor-α, interleukin-1β, interleukin-6, and interleukin-10) to values approaching the control values. Shikimic acid also restored the sodium/potassium-ATPase activity, the apoptosis genes p53 and bcl-2, and the histology of kidney tissue in diarrheal rats to be near the control group.ConclusionsShikimic acid rescues diarrhea and its complications through restoring kidney function, serum and urinary electrolytes, antioxidant activity, inflammatory markers, sodium/potassium-ATPase activity, the apoptosis genes, and the histology of the kidney in diarrheal rats to approach the control one.

Abstract 16169: Use of Ramen in Heart Failure: Correction of Severe Hyponatremia With Salt Intake

Background Hyponatremia (Na<136mmol) is the most common electrolyte imbalance in patients with heart failure (HF) and is associated with increased mortality, morbidity and rehospitalizations. The mechanisms of hyponatremia in heart failure are multifold and include an increased sympathetic tone and renin-angiotensin-aldosterone-system, salt and water retention in the proximal and distal tubules, high antidiuretic hormone coupled low glomerular filtration rate and diuretic use. We present a case highlighting the complexity of sodium balance in acute decompensated heart failure. Case Presentation A 65-year-old female with a medical history of heart failure with preserved ejection fraction (EF 60-65%), pulmonary hypertension, atrial fibrillation, and CKD presented to the Emergency Department with volume overload. We began diuresis with bumetanide on hospital day 1 (HD#), however given inadequate urine output chlorthalidone was added on HD #5 and metolazone on HD #7. On admission, her sodium was 134 and down trended to a low of 121 on HD#13. She had worsening BUN/Cr from 62/2.14 at admission to a peak 135/2.66. She developed oral intake intolerance, asterixis and encephalopathy. The management changed to halting diuretics, fluid restriction, and hypertonic saline without improvement. Urine electrolytes were used to tailor treatment, leading to cessation of hypertonic saline stopped and introducing Ramen (875 mg of Na) and salt tablets (394 mg of Na). While maintaining euvolemia, there was resolution of symptoms and improvement in Na=134, BUN 49, Cr 1.16. Discussion Treatment options for hyponatremia in HF, such as water restriction or the use of hypertonic saline with loop diuretics, have limited efficacy. The use of high oral salt intake with close monitoring of jugular vein pressure, weight, symptoms, and urine electrolytes can help a select group of patients with hyponatremia and advance heart failure despite traditional knowledge.

Critical Role of mTORC2 in Maintaining Sodium and Potassium Balance: Implications for Aldosterone-Independent Regulation of Epithelial Sodium Channel (ENaC) in the Distal Nephron

Critical Role of mTORC2 in Maintaining Sodium and Potassium Balance: Implications for Aldosterone-Independent Regulation of Epithelial Sodium Channel (ENaC) in the Distal Nephron

RELATIONSHIP BETWEEN GRK4 POLYMORPHISMS AND ESSENTIAL HYPERTENSION. A STUDY IN A GROUP OF TURKISH SUBJECTS

Background/Purpose:
 G protein-coupled receptor kinase (GRK4) is associated with essential hypertension (EHT). GRK4 regulates sodium balance in the proximal tubules of the kidney. In this study, the possible roles of A142V and A486V polymorphisms in the development of hypertension were investigated in a Turkish population.
 Methods: Genomic DNA was obtained from white blood cells using the standard DNA isolation kit (Roche). Genotypes of variants of GRK4 were determined by Polymerase chain reaction (PCR) - Restriction fragment length polymorphism (RFLP) analysis. 
 Results: In this study, GRKA142V and A486V polymorphisms were found to be associated with EHT in the Turkish population (P

FRI163 Central Role Of Mirnas During Kidney Development And Establishment Of The Mineralocorticoid Signaling Pathway Establishment Of The Mineralocorticoid Signaling Pathway

Abstract Disclosure: I. Hani: None. T. Vu: None. R. Brillet: None. J. Perrot: None. J. Bouligand: None. J. Guegan: None. N. Cherradi: None. P. Kamenicky: None. M. Lombes: None. L. Martinerie: None. S. Viengchareun: None. In tight epithelia, aldosterone controls sodium and water homeostasis by binding to the Mineralocorticoid Receptor (MR), a steroid nuclear receptor. We have identified a specific temporal window during renal development in which the mineralocorticoid signaling pathway is ineffective due to downregulation of MR expression, explaining physiological sodium wasting observed in human newborns during first days of life. However, underlying molecular mechanisms controlling MR expression remain unknown. Recently, we demonstrated in adult renal KC3AC1 cell line that MR expression is controlled by microRNAs (miR-30c-2-3p and miR-324-5p) in response to variations of tonicity. These regulators bind to 3'-untranslated region (3'-UTR) of MR transcripts to modulate their stability and translation. Therefore, we hypothesized that these miRNAs may be responsible for low expression level of MR at birth, where variations in tonicity are observed due to the transition from intra-amniotic to extra-uterine life. Using primary cultures of renal epithelial cells from neonatal mouse kidneys, harvested at birth (D0) and at Day 8 postnatal (D8), we showed that only miR-30c-2-3p regulates MR expression at D8. For this reason, we performed a complete transcriptomic analysis (miRNA-Seq and RNA-Seq) of kidneys collected at D0 and D8 to identify other miRNAs specifically involved in regulation of MR expression in perinatal period. Bioinformatics analysis allowed us to identify deregulated miRNAs and transcripts between D0 and D8 and to specify their involvement in biological processes and/or signaling pathways. We mainly focused on deregulated miRNAs that may modulate MR expression and affect mineralocorticoid signaling. miR-Seq identified 221 differentially expressed miRNAs. First, we selected 3 over- (miR-431-5p, miR-409-3p, and miR-92a-1-5p) and 3 under-expressed (miR-30a-5p, miR-30e-5p, and miR-802-5p) candidate miRNAs (FDR<0.05 and log2FC>1) having putative binding sites in MR 3'-UTR. Paradoxically, we showed in primary kidney cultures that overexpression of miR-30a-5p, miR-30e-5p, or miR-802-5p increased MR expression (from 50 to 100%, P<0.05) at D0, suggesting that these miRNAs may either positively modulate MR expression or may involve an intermediate regulator. On the opposite, over-expression of miR-92a-1-5p, miR-431-5p, and miR-409-3p at D8 led to a decrease (from 30-40%, P<0.05) in MR expression, suggesting that these miRNAs may modulate MR expression in postnatal period. Currently, we are evaluating whether they could be used as prognostic or severity biomarkers of water loss in neonates by quantifying these candidate miRNAs in urine exosomes of preterm and term infants. A better understanding of mechanisms regulating MR expression in the perinatal period will undoubtedly have a major impact on the management of premature infants with sodium balance maladjustment at birth. Presentation Date: Friday, June 16, 2023

Benefits of Preserving Residual Urine Output in Patients Undergoing Maintenance Haemodialysis.

Chronic kidney disease is a widespread medical problem that leads to higher morbidity, mortality, and a decrease in the overall well-being of the general population. This is especially expressed in patients with end-stage renal disease (ESRD) undergoing maintenance haemodialysis. Several variables could be used to evaluate those patients' well-being and mortality risk. One of them is the presence of residual urine output. The study was conducted on 485 patients treated with maintenance haemodialysis. After enrollment in the study, which consisted of medical history, physical examination, hydration assessment, and blood sampling, each patient was followed up for 24 months. We used residual urine output (RUO) as a measure of residual renal function (RRF). The entire cohort was divided into 4 subgroups based on the daily urinary output (<=100mL per day, >100mL to <=500mL, >500mL to <=1000mL and >1000mL). The data show that the mortality rate was significantly higher in groups with lower RUO, which was caused mainly by cardiovascular events. Also, patients with higher RUO achieved better sodium, potassium, calcium, and phosphate balance. They were also less prone to overhydration and had a better nutritional status. Preserved RRF also had a positive impact on markers of cardiovascular damage, such as NT-proBNP as well as TnT. In conclusion, preserving residual urine output in ESRD patients undergoing maintenance haemodialysis is invaluable in reducing their morbidity and mortality rates and enhancing other favourable parameters of those patients.

Kidney-Specific Membrane-Bound Serine Proteases CAP1/Prss8 and CAP3/St14 Affect ENaC Subunit Abundances but Not Its Activity.

The serine proteases CAP1/Prss8 and CAP3/St14 are identified as ENaC channel-activating proteases in vitro, highly suggesting that they are required for proteolytic activation of ENaC in vivo. The present study tested whether CAP3/St14 is relevant for renal proteolytic ENaC activation and affects ENaC-mediated Na+ absorption following Na+ deprivation conditions. CAP3/St14 knockout mice exhibit a significant decrease in CAP1/Prss8 protein expression with altered ENaC subunit and decreased pNCC protein abundances but overall maintain sodium balance. RNAscope-based analyses reveal co-expression of CAP3/St14 and CAP1/Prss8 with alpha ENaC in distal tubules of the cortex from wild-type mice. Double CAP1/Prss8; CAP3/St14-deficiency maintained Na+ and K+ balance on a Na+-deprived diet, restored ENaC subunit protein abundances but showed reduced NCC activity under Na+ deprivation. Overall, our data clearly show that CAP3/St14 is not required for direct proteolytic activation of ENaC but for its protein abundance. Our study reveals a complex regulation of ENaC by these serine proteases on the expression level rather than on its proteolytic activation.

Association study of WNK1 genetic variants and essential hypertension risk in the Northern Han Chinese in Beijing.

Background: Essential hypertension (EH) is a complex disorder resulting from interaction of genetic and environmental factors. Lysine deficient protein kinase 1 (WNK1) plays a very important role in maintaining renal potassium, sodium and chlorine ions balance as well as the regulation of blood pressure, so the WNK1 gene is considered a key gene for EH. This study thus sought to evaluate possible genetic associations between the WNK1 genetic variants and EH risk in the Northern Han Chinese population in Beijing. Methods: This study included 476 hypertensive subjects and 491 normotensive subjects. A total of 12 tag SNVs of WNK1 gene were genotyped successfully by TaqMan assay. Comparisons of the genotypic and allelic frequency between cases and controls were made by using the chi-square test. Logistic regression analyses were performed under different genetic models, and haplotype analysis was also conducted. Results: A total of 12 SNVs were identified as the tag SNVs for WNK1 gene. Significant associations were observed between WNK1 gene rs7305099 variant and EH risk, and T allele influenced hypertension risk in a protective manner. After correcting for multiple testing using Bonferroni, the significance remained for the SNV of rs7305099 in three genetic models [allele comparison, p < 0.0002, OR = 0.627, 95%CI (0.491-0.801); homozygote comparison, p < 0.0003, OR = 0.278, 95%CI (0.140-0.552); additive model, p < 0.0003, OR = 0.279, 95%CI (0.140-0.553)]. In the haplotype analyses, we found that the haplotype A-A-A-C-G-G-G was significantly associated with increased risk for EH (p = 0.043, OR = 1.23). Conclusion: Our data suggested that the rs7305099 genetic variant and the haplotype A-A-A-C-G-G-G on WNK1 gene might be associated with the susceptibility of EH in the Northern Han Chinese population. These could provide evidences to the risk assessment, early prevention and individualized therapy of EH to some extent.

The organum vasculosum of the lamina terminalis and subfornical organ: regulation of thirst.

Thirst and water intake are regulated by the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ (SFO), located around the anteroventral third ventricle, which plays a critical role in sensing dynamic changes in sodium and water balance in body fluids. Meanwhile, neural circuits involved in thirst regulation and intracellular mechanisms underlying the osmosensitive function of OVLT and SFO are reviewed. Having specific Nax channels in the glial cells and other channels (such as TRPV1 and TRPV4), the OVLT and SFO detect the increased Na+ concentration or hyperosmolality to orchestrate osmotic stimuli to the insular and cingulate cortex to evoke thirst. Meanwhile, the osmotic stimuli are relayed to the supraoptic nucleus (SON) and paraventricular nucleus of the hypothalamus (PVN) via direct neural projections or the median preoptic nucleus (MnPO) to promote the secretion of vasopressin which plays a vital role in the regulation of body fluid homeostasis. Importantly, the vital role of OVLT in sleep-arousal regulation is discussed, where vasopressin is proposed as the mediator in the regulation when OVLT senses osmotic stimuli.

Body weight reduction by exercise increases the urinary 3-methylhistidine excretion level with relatively positive nitrogen, sodium, and potassium balances when compared to dietary restriction

BackgroundRegarding changes in muscle mass, differences due to types of exercise and/or nutritional interventions, and associations with nutrient balances are still unclear. MethodsTo estimate changes in muscle mass during a body weight loss program using either a diet or exercise regimen, we investigated levels of muscle mass-related indices, and body contents of nitrogen, sodium, and potassium as measured by the balance method. Six healthy young adult male volunteers participated in two 10-day crossover experiments (20 days total). The first 5 days comprised an adjustment period (energy intake, 2656 ± 367 kcal/day (mean ± standard deviation)). During the second 5-day period, the participants either reduced their energy intake to 1770 ± 244 kcal/day (diet regimen) or exercised on a bicycle ergometer to expend 886 ± 122 kcal/day (exercise regimen). ResultsThe nitrogen, sodium, and potassium balances were significantly more positive during the exercise regimen than during the diet regimen. The urinary excretion levels of creatinine, 3-methylhistidine (3-MH), aldosterone, and catecholamines, and the 3-MH/creatinine ratio were significantly increased only during the exercise regimen. ConclusionsThe exercise regimen suppresses the decrease in muscle mass-related indices during body weight loss compared to the diet regimen with a relatively positive state of whole-body protein, sodium, and potassium balances, accompanied by an increase in sympathetic/adrenal cortical functions.

Triphasic response after endoscopic craniopharyngioma resection and its dependency on infundibular preservation or sacrifice.

Surgery is the primary treatment for craniopharyngioma with the preservation of hypothalamic function of paramount importance. Infundibular preservation is debated, as maximal resection decreases recurrence rates but causes hypopituitarism. A triphasic response of diabetes insipidus (DI), syndrome of inappropriate antidiuretic hormone secretion (SIADH), and recurrent DI has been described after pituitary surgery, but the impact of infundibular preservation on the triphasic response following craniopharyngioma resection has not been well established. The authors' objective was to assess postoperative fluid and sodium balance and differences in ADH imbalance management following endonasal craniopharyngioma resection based on infundibular transection status. This is a retrospective cohort study of 19 patients with craniopharyngioma treated with endoscopic endonasal resection between 2014 and 2021. Resection was dichotomized into infundibular transection or preservation. Postoperative triphasic response, time to DI, and time to ADH replacement were compared using Fisher's exact test and Kaplan-Meier analysis. Based on surgeon impression, 10 patients had infundibular transection and 9 had infundibular preservation. Overall, 16 patients experienced DI, 12 experienced persistent DI, and 6 experienced SIADH. A postoperative triphasic response occurred in 40% (n = 4) of transection patients without preoperative DI and 11% (n = 1) of preservation patients without preoperative DI. The median time to postoperative DI (0.5 vs 18.0 hours, p = 0.022) and median time to ADH replacement therapy (4.5 vs 24 hours, p = 0.0004) were significantly shorter in the transection group than in the preservation group. Following endonasal craniopharyngioma resection, the triphasic response occurs in nearly half of infundibular transection cases. DI begins earlier with infundibular transection. On the basis of the study findings in which no patients met the criteria for SIADH or were endocrinologically unstable after postoperative day 6, it is reasonable to suggest that otherwise stable patients can be discharged at or before postoperative day 6 when ADH fluctuations have normalized and endocrinopathy is appropriately managed with oral desmopressin. Infundibular transection status may impact postoperative hormonal replacement strategies, but additional studies should evaluate their efficacies.

Sodium accumulation in the skin is associated with higher density of skin lymphatic vessels in patients with arterial hypertension

PurposeRecent studies, conducted mainly on the rodent model, have demonstrated that regulatory pathway in the skin provided by glycosaminoglycans, nuclear factor of activated T cells 5 (NFAT5), vascular endothelial growth factor C (VEGF-C) and process of lymphangiogenesis may play an important role in extrarenal regulation of sodium (Na+) balance, body water volume, and blood pressure. We aimed to investigate the concentrations and relations among the main factors of this pathway in human skin to confirm that this regulatory axis also exists in humans. Patients and methodsSkin specimens from patients diagnosed with arterial hypertension and from control group were histologically and molecularly examined. ResultsThe primary hypertensive and control groups did not differ in Na+ ​concentrations in the skin. However, the patients with hypertension and higher skin Na+ concentration had significantly greater density of skin lymphatic vessels. Higher skin Na+concentration was associated with higher skin water content. In turn, skin water content correlated with factors associated with lymphangiogenesis, i.e. NFAT5, VEGF-C, and podoplanin (PDPN) mRNA expression in the skin. The strong mutual pairwise correlations of the expressions of NFAT5, VEGF-C, vascular endothelial growth factor D (VEGF-D) and PDPN mRNA were noted in the skin in all of the studied groups. ConclusionsOur study confirms that skin interstitium and the lymphatic system may be important players in the pathophysiology of arterial hypertension in humans. Based on the results of our study and existing literature in this field, we propose the hypothetical model which might explain the phenomenon of salt-sensitivity.

NPRA promotes fatty acid metabolism and proliferation of gastric cancer cells by binding to PPARα

Among cancers, gastric cancer (GC) ranks third globally in morbidity and mortality, particularly in East Asia. Natriuretic peptide receptor A (NPRA), a receptor for guanylate cyclase, plays important roles in regulating water and sodium balance. Recent studies have suggested that NPRA is involved in tumorigenesis, but its role in GC development remains unclear. Herein, we showed that the expression level of NPRA was positively correlated with gastric tumor size and clinical stage. Patients with high NPRA expression had a lower five-year survival rate than those with low expression, and NPRA was identified as an independent predictor of GC prognosis. NPRA knockdown suppressed GC cell proliferation, migration and invasion. NPRA overexpression enhanced cell malignant behavior. Immunohistochemistry of collected tumor samples showed that tumors with high NPRA expression had higher peroxisome proliferator-activated receptor α (PPARα) levels. In vivo and in vitro studies showed that NPRA promotes fatty acid oxidation and tumor cell metastasis. Co-IP showed that NPRA binds to PPARα and prevents PPARα degradation. PPARα upregulation under NPRA protection activates arnitine palmitoyl transferase 1B (CPT1B) to promote fatty acid oxidation. In this study, new mechanisms by which NPRA promotes the development of GC and new regulatory mechanisms of PPARα were identified.