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Background/Objectives: Blood pressure (BP) is characterized by a circadian rhythm (Circr) with lower nighttime values, called dipping. Non-dipping is associated with higher CVD risk. The Circr of urinary sodium excretion (NaCle), peaking during the day, is linked to BP patterns. Physical activity (PA) is known to improve BP control and enhance the dipping phenomenon, but its possible effect on NaCle remains unclarified. This study aimed to investigate the correlation between PA and the Circr of NaCle and to determine if the relationship is independent of age, sex, BP values, dipping pattern, and salt intake. Methods: A pilot cross-sectional analysis was conducted using data from the Ticino Epidemiological Stiffness Study, involving 953 participants in Switzerland. Data collection included standardized questionnaires, blood samples, 24 h urine collections, and ambulatory BP monitoring. Participants were categorized into sedentary, partially active, and active. The effect of PA, NaCl intake, and dipping on the day/night NaCle ratio was assessed with multivariable linear regressions. Results: Participants' median age was 49 years, with 78% having normal BP values and 47% exhibiting a dipping pattern; 51% were classified as sedentary and 22% as partially active. The median NaCl intake was 7.9 g/day. The youngest subjects had a higher hourly NaCle ratio compared to older subjects. Higher NaCl intake correlated with increased BP, a phenomenon more pronounced in men and younger subjects. The hourly day/night NaCle ratio positively correlates with dipping; however, PA did not show a significant correlation with the NaCle ratio. Conclusions: This study indicates that while the day/night NaCle ratio correlates with the dipping pattern, PA is unrelated to the circadian rhythm of renal sodium handling. The beneficial effects of PA on BP and cardiovascular health thus appear to be mediated through mechanisms other than NaCle. These are explorative findings only but relativize the need for further investigations on the topic. [ABSTRACT FROM AUTHOR]

Introduction: Renal function may be compromised following recovery from kidney insults. Renal functional reserve (RFR) is a measure of the difference between the kidney's maximum capacity and its baseline function, which helps identify any areas of the kidney with compromised function. Usually, RFR is evaluated using acute volume expansion (AVE), but this is typically done in anesthetized animals, which may not accurately represent the kidney's complete functional capacity. In this study, we have introduced a novel method that enables AVE to be conducted in conscious mice. Methods: We have implemented this innovative approach in two animal models representing either intact or impaired renal function, specifically utilizing a lower nephron hypertensive model. Mice were implanted with radio-transmitters for mean artery blood pressure (MAP) monitoring during the experiment. After recovery, half of the mice were induced hypertension by right kidney nephrectomy combined with the ligation of the upper branch of the left kidney. For the AVE, a volume equivalent to 5% of the mouse's body weight was administered via intravenous (IV) or intraperitoneal bolus injection. Subsequently, the mice were individually housed in cages covered with plastic wrap. Urine was collected every hour for a total of 3 h for the measurement of urine and sodium excretion. Results: The MAPs for all normotensive mice were consistent throughout the AVE, but it increased 5–16 mm Hg in the hypertensive mice upon AVE. Remarkably, conscious mice exhibited a significantly stronger response to IV-administered AVE when compared to anesthetized mice. This response was evident in the increase in urinary flow, which was approximately 170% and 145% higher in conscious normotensive and hypertensive mice, respectively, compared to their respective baselines. In contrast, anesthetized normotensive and hypertensive mice showed only around a 130% and 100% increase in urinary flow, respectively. Additionally, upon AVE, conscious normotensive mice excreted approximately 47% more sodium than conscious hypertensive mice. In contrast, anesthetized normotensive mice excreted only about 30% more sodium than their anesthetized hypertensive counterparts. Conclusion: Performing a kidney stress test with a significant solution load in conscious mice seems to be a superior method for evaluating RFR compared to conducting the test under anesthesia. Assessing kidney clearance while the mice are conscious has the potential to enhance the precision of diagnosing and predicting both acute and chronic kidney diseases. [ABSTRACT FROM AUTHOR]

High sodium intake is an accepted risk factor for hypertension, while low Na+ intake has also been associated with increased risk of cardiovascular events. In this cross-sectional study, we examined the association of 24-h urinary Na+ excretion with haemodynamics and volume status. Haemodynamics were recorded in 510 normotensive and never-treated hypertensive subjects using whole-body impedance cardiography and tonometric radial artery pulse wave analysis. The results were examined in sex-specific tertiles of 24-h Na+ excretion, and comparisons between normotensive and hypertensive participants were also performed. Regression analysis was used to investigate factors associated with volume status. The findings were additionally compared to 28 patients with primary aldosteronism. The mean values of 24-h urinary Na+ excretion in tertiles of the 510 participants were 94, 148 and 218 mmol, respectively. Average tertile age (43.4–44.7 years), office blood pressure and pulse wave velocity were corresponding in the tertiles. Plasma electrolytes, lipids, vitamin D metabolites, parathyroid hormone, renin activity, aldosterone, creatinine and insulin sensitivity did not differ in the tertiles. In supine laboratory recordings, there were no differences in aortic systolic and diastolic blood pressure, heart rate, cardiac output and systemic vascular resistance. Extracellular water volume was higher in the highest versus lowest tertile of Na+ excretion. In regression analysis, body surface area and 24-h Na+ excretion were independent explanatory variables for extracellular water volume. No differences in urine Na+ excretion and extracellular water volume were found between normotensive and hypertensive participants. When compared with the 510 participants, patients with primary aldosteronism had 6.0% excess in extracellular water (p =.003), and 24-h Na+ excretion was not related with extracellular water volume. In the absence of mineralocorticoid excess, Na+ intake, as evaluated from 24-h Na+ excretion, predominantly influences extracellular water volume without a clear effect on blood pressure. We evaluated sodium intake in 510 subjects by measuring their 24-h sodium excretion to the urine and examined whether sodium intake was related with alterations in cardiovascular function and fluid balance. All participants were without blood pressure lowering medications. Blood pressure was recorded by a device that senses the radial artery pulsations form the wrist. The amount of blood pumped by the heart, the transfer of pressure waves following cardiac contractions and body fluid status were evaluated using bioimpedance, a method recording changes in body electrical resistance. For the analyses, the participants were divided into tertiles according to their 24-h sodium excretions. We also compared results between normotensive and hypertensive subjects. The 24-h sodium excretion in the tertiles corresponded to about 6 g, 9 g and 13 g of salt intake per day, respectively. There were no differences between the tertiles in age, routine laboratory analyses, blood pressure, large arterial stiffness, amount blood pumped by the heart and resistance to blood flow in the arteries. However, there was more extracellular fluid in the highest versus the lowest tertile of sodium excretion. Further statistics indicated that extracellular fluid volume in the body was mainly determined by body size, but it was also moderately influenced by sodium intake. No differences in 24-h sodium excretion and extracellular water volume were found between normotensive and hypertensive participants. In subjects not using blood pressure lowering medications, sodium intake predominantly influences the amount of extracellular fluid without a clear effect on blood pressure. [ABSTRACT FROM AUTHOR]

Purpose High sodium intake is an accepted risk factor for hypertension, while low Na+ intake has also been associated with increased risk of cardiovascular events. In this cross-sectional study, we examined the association of 24-h urinary Na+ excretion with haemodynamics and volume status. Materials and methods Haemodynamics were recorded in 510 normotensive and never-treated hypertensive subjects using whole-body impedance cardiography and tonometric radial artery pulse wave analysis. The results were examined in sex-specific tertiles of 24-h Na+ excretion, and comparisons between normotensive and hypertensive participants were also performed. Regression analysis was used to investigate factors associated with volume status. The findings were additionally compared to 28 patients with primary aldosteronism. Results The mean values of 24-h urinary Na+ excretion in tertiles of the 510 participants were 94, 148 and 218 mmol, respectively. Average tertile age (43.4–44.7 years), office blood pressure and pulse wave velocity were corresponding in the tertiles. Plasma electrolytes, lipids, vitamin D metabolites, parathyroid hormone, renin activity, aldosterone, creatinine and insulin sensitivity did not differ in the tertiles. In supine laboratory recordings, there were no differences in aortic systolic and diastolic blood pressure, heart rate, cardiac output and systemic vascular resistance. Extracellular water volume was higher in the highest versus lowest tertile of Na+ excretion. In regression analysis, body surface area and 24-h Na+ excretion were independent explanatory variables for extracellular water volume. No differences in urine Na+ excretion and extracellular water volume were found between normotensive and hypertensive participants. When compared with the 510 participants, patients with primary aldosteronism had 6.0% excess in extracellular water (p = .003), and 24-h Na+ excretion was not related with extracellular water volume. Conclusion In the absence of mineralocorticoid excess, Na+ intake, as evaluated from 24-h Na+ excretion, predominantly influences extracellular water volume without a clear effect on blood pressure.

Purpose: To assess any effects of a state-wide sodium reduction intervention on sodium intake, sources of dietary sodium and discretionary salt use at a population level. Methods: Data (24-h urinary sodium excretion, self-report survey, a 24-h dietary recall) were collected cross-sectionally at baseline (2016/2017) and follow-up (2020) from adults in Victoria, Australia. Intervention activities included consumer awareness advertising campaign, public debate generation via mass media, strengthening existing policy initiatives and supporting food innovation with industry. Results: There were 339 participants at baseline and 211 at follow-up, with 144 and 90 of participants completing a 24-h dietary recall, respectively. There was no difference in adjusted 24-h urinary sodium excretion between baseline and follow-up (134 vs 131 mmol/24 h; p = 0.260). There were no differences in the percentage of participants adding salt during cooking (63% vs 68%; p = 0.244), adding salt at the table (34% vs 37%; p = 0.400) or regularly taking action to control salt/sodium intake (22% vs 21%; p = 0.793). There were large differences in the quantity of dietary sodium sourced from retail stores (57% vs 77%, p < 0.001), and less sodium was sourced from foods at fresh food markets (13% vs 2%; p ≤ 0.001) at follow-up. No large differences were apparent for foods with different levels of processing or for food groups. Conclusion: There was no clear population-level effect of the 4-year multi-component Victorian Salt Reduction Intervention on sodium intake with Victorian adults continuing to consume sodium above recommended levels. The findings indicate that more intensive and sustained efforts aiming at the retail and food industry with national level support are likely to be required to achieve a measurable improvement in sodium intake at a state level. [ABSTRACT FROM AUTHOR]

Hypertension is an important morbidity factor. The prognostic consequences of the white-coat effect have been studied extensively. The repercussion on the circadian rhythm of urinary water and salt excretion in the same subgroup remain, conversely, among the open topics. Postulating an impaired diurnal sodium and volume excretion we decided to investigate both, in subjects with or without a white-coat effect, in the general population. A sample of 1023 subjects, has been considered. We collected 24-h urine samples, divided in day and night, and we measured the blood pressure with an Ambulatory Blood Pressure Monitoring (ABPM). ABPM values were then compared with physician collected in-office values to assign subjects to the group with or without the white-coat effect. Concerning the circadian pattern of urinary sodium excretion, we found no significant differences between the groups. There was instead in the white-coat effect group a higher night/day ratio of urinary water excretion. The white-coat effect, has been considered a potential hypertension precursor, and its consequent handling could be prospectively relevant in hypertension prevention. The absence of repercussions on the urinary circadian sodium excretion pattern and on the potentially related risk factors in subjects with a white coat effect is reassuring. The clinical significance of the impact on the night/day ratio of water excretion needs to be further investigated. [ABSTRACT FROM AUTHOR]

Purpose: Gastric atrophy (GA), usually linked to chronic infection with Helicobacter pylori (H. pylori), may over time evolve into gastric malignancy. Besides H. pylori, high salt intake may play a role in GA development. This study evaluates cross sectionally the association between salt intake and GA in Chilean adults. Methods: Population-based samples were recruited from two sites, Antofagasta and Valdivia, partaking in the Epidemiological Investigation of Gastric Malignancies. At recruitment, participants answered questionnaires and provided biospecimens. Salt intake (g/day) was estimated from casual spot urine samples using the Tanaka equation. GA was determined by serum pepsinogen levels. Only participants ≥ 40 to 70 years of age were considered in this analysis, n = 565. For the association between salt intake (as sex-specific quartiles) and GA, odds ratios (ORs) and the corresponding 95% confidence intervals (CI) were estimated through multivariable logistic regression. Results: In women, the multivariable-adjusted OR for GA comparing quartile 4 of the estimated salt intake (12.8 g/day) to quartile 1 (6.6 g/day) was 1.18 (95% CI 0.52–2.68, P-trend = 0.87). The corresponding OR in men was 0.49 (95% CI 0.19–1.27, P-trend = 0.17) with salt intakes of 12.8 g/day and 7.1 g/day for quartiles 4 and 1, respectively. Conclusion: There was little evidence for an association between salt intake estimated from spot urine and GA risk in our cross-sectional analysis of middle aged and older adults in Chile. Reverse causation bias cannot be ruled out and the sample size was limited to provide more precise estimates. [ABSTRACT FROM AUTHOR]

Simple Summary: Sodium homeostasis is critical for body fluid balance. The hormonal regulation of sodium reabsorption and excretion is central in sodium homeostasis. The kidney is the main organ that controls sodium reabsorption and excretion. Corin is a proteolytic enzyme responsible for activating atrial natriuretic peptide (ANP), a key hormone that promotes renal natriuresis. The heart is the main organ for corin and ANP expression. In this work, we report that corin and ANP are expressed in the mouse intestine, where sodium excretion also occurs. Corin deficiency impairs fecal sodium excretion in mice. These findings reveal a new function of corin in the intestinal tract to promote sodium excretion. Sodium excretion, a critical process in sodium homeostasis, occurs in many tissues, including the kidney and intestine. Unlike in the kidney, the hormonal regulation of intestinal sodium excretion remains unclear. Atrial natriuretic peptide (ANP) is a crucial hormone in renal natriuresis. Corin is a protease critical for ANP activation. Corin and ANP are expressed mainly in the heart. In this study, we investigated corin, ANP, and natriuretic peptide receptor A (Npra) expression in mouse intestines. Corin and ANP expression was co-localized in enteroendocrine cells, whereas Npra expression was on the luminal epithelial cells. In Corin knockout (KO) mice, fecal Na+ and Cl− excretion decreased compared with that in wild-type (WT) mice. Such a decrease was not found in conditional Corin KO mice lacking cardiac corin selectively. In kidney conditional Corin KO mice lacking renal corin, fecal Na+ and Cl− excretion increased, compared to that in WT mice. When WT, Corin KO, and the kidney conditional KO mice were treated with aldosterone, the differences in fecal Na+ and Cl− levels disappeared. These results suggest that intestinal corin may promote fecal sodium excretion in a paracrine mechanism independent of the cardiac corin function. The increased fecal sodium excretion in the kidney conditional Corin KO mice likely reflected an intestinal compensatory response to renal corin deficiency. Our results also suggest that intestinal corin activity may antagonize aldosterone action in the promotion of fecal sodium excretion. These findings help us understand the hormonal mechanism controlling sodium excretion the intestinal tract. [ABSTRACT FROM AUTHOR]

Several studies have shown inorganic nitrate/nitrite to reduce blood pressure in both healthy subjects and hypertensive patients. An effect presumably caused through bioconversion to nitric oxide. However, studies on inorganic nitrate/nitrite have shown inconsistent results on renal functions such as GFR and sodium excretion. The current study investigated whether orally administered nitrate would decrease blood pressure and increase GFR and urinary sodium excretion. In a randomized, placebo-controlled, double-blinded, crossover study, 18 healthy subjects received a daily dose of 24 mmol potassium nitrate and placebo (potassium chloride) during 4 days in a randomized order. Subjects also ingested a standardized diet and completed a 24-h urine collection. GFR was determined by the constant infusion technique and during GFR measurement, brachial blood pressure (BP) and central blood pressure (cBP), heart rate, and arterial stiffness were measured every half hour using the Mobil-O-Graph®. Blood samples was analyzed for nitrate, nitrite, cGMP, vasoactive hormones and electrolytes. Urine was analyzed for nitrate, nitrite, cGMP, electrolytes, ENaC γ , NCC, CrCl, C H2O and UO. No differences in GFR, blood pressure or sodium excretion were found between the treatments with potassium nitrate and placebo. However, both nitrate and nitrite levels in plasma and urine were significantly increased by potassium nitrate intake and the 24-h urinary excretion of sodium and potassium were stable, showing adherence to the standardized diet and the study medication. We found no decrease in blood pressure or increase in GFR and sodium excretion of 24 mmol potassium nitrate capsules as compared to placebo after 4 days of treatment. Healthy subjects may be able to compensate the effects of nitrate supplementation during steady state conditions. Future research should focus on long-term studies on the difference in response between healthy subjects and patients with cardiac or renal disease. • Potassium nitrate supplementation increased both plasma nitrate and nitrite. • No reduction of blood pressure was found after 4 days' 24 mmol potassium nitrate. • Potassium nitrate did not increase GFR or sodium excretion. [ABSTRACT FROM AUTHOR]

Although changes in dietary sodium intake alter blood pressure (BP) in salt-sensitive individuals, pathophysiological mechanisms are still unknown. It has been reported that uromodulin is involved in sodium tubular transport, and genome-wide association studies pointed to UMOD gene as one of the most important gene candidates for arterial hypertension. Our aim was to analyze urinary uromodulin, salt intake and BP in 326 young middle-aged subjects (mean age 36±8 years, 49.4% male). In a subgroup of 175 individuals, ambulatory blood pressure monitoring and echocardiogram were performed. Uromodulin was determined by ELISA. According to the JNC-7 criteria, subjects were classified as optimal BP (n=103, men 72%), prehypertension (PHT) (n=143, men 43%) and hypertension (HT) (n= 80, men 38%). There were no differences in age, salt intake, estimated glomerular filtration rate, sodium excretion and uromodulin among BP groups. However, in PHT subjects, uromodulin was positively associated with fractional sodium excretion and negatively with 24-h sodium excretion and diastolic BP dip. These findings point to the effect of uromodulin on sodium reabsorption along the nephron and consequently circadian BP alteration in prehypertensives.

The 20th century is the time of the birth of many scientific areas, including the physiology of the kidneys and water-salt metabolism. This article is devoted to the history of the development of one of its directions - the issue of regulation of sodium homeostasis in the body. This article is the first attempt in the Russianspeaking space to summarize the achievements in the study of sodium regulation. For many decades, scientists from different countries have studied the influence of various factors on sodium excretion: blood pressure, atrial peptides, hormones of the neurohypophysis and adrenal glands, renal nerves, infusion of various substances, etc. It was found that sodium excretion does not directly depend on changes in blood pressure and glomerular filtration rate. Atrial peptides causing natriuresis were discovered, their structure and mechanism of action were described in detail. The role of the hormones of the neurohypophysis - vasopressin and oxytocin - in the excretion of sodium, as well as the role of aldosterone and angiotensin II in the reabsorption of this cation was shown. It has been shown that the administration of hypertonic solutions of sodium chloride causes a greater natriuretic response than the administration of other substances (sodium sulfate and acetate, glucose, mannitol, etc.), and the idea of the existence of sodium-s ensitive receptors has also been put forward.

Natriuresis is closely linked to glomerular hemodynamics in diabetic kidney disease (DKD), and is known to be influenced by inhibition of sodium-glucose cotransporter 2 (SGLT2) or dipeptidyl peptidase-4 (DPP-4). In the present study, we investigated whether dual inhibition of SGLT2 and DPP-4 exerts an additive effect on promoting natriuresis and how it ameliorates glomerular hemodynamic abnormalities via the natriuretic effect in DKD. Eight-week-old male KK/Ta- Ins2 Akita (KK/Ta-Akita) mice which develop progressive DKD were orally once-daily given either SGLT2 inhibitor empagliflozin (30 mg/kg) alone, DPP-4 inhibitor linagliptin (5 mg/kg) alone or a combination of empagliflozin (30 mg/kg) plus linagliptin (5 mg/kg) for 6 weeks. In vehicle-treated control KK/Ta-Akita mouse group, markedly enhanced glomerular albumin filtration and glomerular filtration rate (GFR) were observed. These renal alterations were dramatically attenuated in KK/Ta-Akita mouse group treated with a combination of empagliflozin plus linagliptin. Notably, the combination therapy provided greater reduction in glomerular albumin filtration and GFR along with higher urinary excretion of sodium and a potential afferent arteriolar vasoconstrictor adenosine than the empagliflozin monotherapy. Significant reduction in urinary excretion levels of a potential afferent arteriolar vasodilator prostaglandin E2 (PGE2) relative to the baseline values was observed after the combination therapy but not the monotherapy. These results suggest that dual inhibition of SGLT2 and DPP-4 highly promotes a distal tubular sodium delivery and thereby contributes to the appropriate modulation of preglomerular arteriolar tone and intraglomerular pressure via an increase in adenosine release and a reduction in PGE2 secretion from macula densa in DKD. • Dual SGLT2 and DPP-4 inhibition exerts an additive effect on promoting natriuresis. • Enhanced natriuresis increases an afferent arteriolar vasoconstrictor release. • Enhanced natriuresis reduces an afferent arteriolar vasodilator secretion. • Such renal alterations attenuate intraglomerular hypertension in DKD. • Dual SGLT2 and DPP-4 inhibition offers higher renal benefits than SGLT2 inhibition. [ABSTRACT FROM AUTHOR]

The activity of the epithelial Na+ channel (ENaC) in principal cells of the distal nephron fine-tunes renal Na+ excretion. The renin-angiotensin-aldosterone system modulates ENaC activity to control blood pressure, in part, by influencing Na+ excretion. NADPH oxidase activator 1-dependent NADPH oxidase 1 (NOXA1/NOX1) signaling may play a key role in angiotensin II (ANG II)- dependent activation of ENaC. The present study aimed to explore the role of NOXA1/NOX1 signaling in ANG II-dependent activation of ENaC in renal principal cells. Patch-clamp electrophysiology and principal cell-specific Noxa1 knockout (PC-Noxa1 KO) mice were used to determine the role of NOXA1/NOX1 signaling in ANG II-dependent activation of ENaC. The activity of ENaC in the luminal plasma membrane of principal cells was quantified in freshly isolated split-opened tubules using voltage-clamp electrophysiology. ANG II significantly increased ENaC activity. This effect was robust and observed in response to both acute (40 min) and more chronic (48–72 h) ANG II treatment of isolated tubules and mice, respectively. Inhibition of ANG II type 1 receptors with losartan abolished ANG II-dependent stimulation of ENaC. Similarly, treatment with ML171, a specific inhibitor of NOX1, abolished stimulation of ENaC by ANG II. Treatment with ANG II failed to increase ENaC activity in principal cells in tubules isolated from the PC-Noxa1 KO mouse. Tubules from wild-type littermate controls, though, retained their ability to respond to ANG II with an increase in ENaC activity. These results indicate that NOXA1/NOX1 signaling mediates ANG II stimulation of ENaC in renal principal cells. As such, NOXA1/NOX1 signaling in the distal nephron plays a central role in Na+ homeostasis and control of blood pressure, particularly as it relates to regulation by the renin-ANG II axis. NEW & NOTEWORTHY Activity of the epithelial Na+ channel (ENaC) in the distal nephron fine-tunes renal Na+ excretion. Angiotensin II (ANG II) has been reported to enhance ENaC activity. Emerging evidence suggests that NADPH oxidase (NOX) signaling plays an important role in the stimulation of ENaC by ANG II in principal cells. The present findings indicate that NOX activator 1/NOX1 signaling mediates ANG II stimulation of ENaC in renal principal cells. [ABSTRACT FROM AUTHOR]

Background The intake of Saccharina japonica (SJ), a widely consumed brown seaweed, has been reported to decrease blood pressure (BP) in hypertensive rats. It has been suggested that this effect is related to an increase in fecal sodium excretion (SE) by alginate (Alg) to the gastrointestinal tract; however, the mechanism is still unclear. This study investigated how different seaweeds with different amounts of Alg suppressed BP increase and enhanced fecal SE in 2-kidney, 1-clip renovascular hypertensive (2K1C) rats given SJ diet. Methods Rats with 2K1C or sham operation were fed a normal-/high-salt diet with some kinds of seaweeds (5.0%, w/w) or SJ extract with different Alg contents for 6 weeks. We measured systolic BP every week and mean arterial pressure at the end, and measured the total and molecular weights of Alg in each seaweed. Then, we evaluated the relationship of the Alg amount in each seaweed with the suppression of BP increase in 2K1C rats. Finally, urinary and fecal SE for 24 h was measured. Results The intake of SJ, SJ extract, Saccharina ochotensis (SO) blades and SO roots suppressed BP increase in 2K1C rats, but the strength was not proportional to the amounts of Alg contained in the seaweeds. Although SJ intake increased fecal SE in 2K1C rats fed a high-salt diet, the fecal SE was much less than urinary SE. Conclusion The sodium excretion in feces by Alg in SJ may not be one of the major mechanisms by which SJ intake attenuates hypertension in 2K1C rats.

Sodium excretion, a critical process in sodium homeostasis, occurs in many tissues, including the kidney and intestine. Unlike in the kidney, the hormonal regulation of intestinal sodium excretion remains unclear. Atrial natriuretic peptide (ANP) is a crucial hormone in renal natriuresis. Corin is a protease critical for ANP activation. Corin and ANP are expressed mainly in the heart. In this study, we investigated corin, ANP, and natriuretic peptide receptor A (Npra) expression in mouse intestines. Corin and ANP expression was co-localized in enteroendocrine cells, whereas Npra expression was on the luminal epithelial cells. In Corin knockout (KO) mice, fecal Na+ and Cl− excretion decreased compared with that in wild-type (WT) mice. Such a decrease was not found in conditional Corin KO mice lacking cardiac corin selectively. In kidney conditional Corin KO mice lacking renal corin, fecal Na+ and Cl− excretion increased, compared to that in WT mice. When WT, Corin KO, and the kidney conditional KO mice were treated with aldosterone, the differences in fecal Na+ and Cl− levels disappeared. These results suggest that intestinal corin may promote fecal sodium excretion in a paracrine mechanism independent of the cardiac corin function. The increased fecal sodium excretion in the kidney conditional Corin KO mice likely reflected an intestinal compensatory response to renal corin deficiency. Our results also suggest that intestinal corin activity may antagonize aldosterone action in the promotion of fecal sodium excretion. These findings help us understand the hormonal mechanism controlling sodium excretion the intestinal tract.

Purpose: Mild-to-moderate iodine deficiency was present in large parts of Germany up to the beginning 1990s and improved from then on. Current epidemiological data on spot urine iodine measurements in German children strongly suggest the re-occurrence of an impaired iodine status. We thus examined whether this re-occurrence is identifiable in more detail, through iodine analyses of 24-h urine samples of a well-characterized cohort of German children in whom samples have been systematically collected from 1985 onward. As iodized salt is a major source for iodine supply, urinary sodium excretion was additionally studied. Methods: Daily iodine and sodium excretions were measured in 2600 24-h urine samples collected between 1985 and 2018 by 677 healthy children aged 6–12 years (participants of the DONALD study). These data were compared with 24-h iodine and sodium excretion estimates obtained from spot urine samples collected in the representative German Health Interview and Examination Surveys for Children and Adolescents KiGGS-baseline (2003–2006) and KiGGS-wave-2 (2014–2017). Results: Between 1985 and1992, DONALD participants started with a median daily iodine excretion level of 40.1 µg/d. Then, during 1993–2003, iodine excretions mounted up to an approximate plateau (~ 84.8 µg/d). This plateau lasted until 2012. Thereafter, iodine concentrations started to decrease again resulting in a median iodine excretion of only 58.9 µg/d in 2018. Sodium excretion, however, had increased. The marked decrease in iodine status along with an abundant sodium excretion corresponded closely with nationwide KiGGS data. Conclusions: As exemplified for the clearly worsening iodine status in German children, longitudinal cohort studies collecting detailed biomarker-based prospective data have the potential to reliably capture health-relevant nutritional changes and trends, applicable on a more comprehensive and even representative population level. [ABSTRACT FROM AUTHOR]

Background: The choice of anaesthetic may influence regulation of renal perfusion and function. We investigated renal function in patients anaesthetised with propofol or sevoflurane before surgery and postoperatively.Methods: Patients with ASA physical status 1-2 planned for spinal surgery were randomised to propofol or sevoflurane anaesthesia. Blood and urine were collected before anaesthesia, during anaesthesia (before surgery), during postoperative care, and the day after surgery.Results: Twenty-seven patients completed the study protocol (average age, 51 yr; average BMI, 28 kg m-2) and 11 were women. Urine output and sodium excretion were lower during sevoflurane anaesthesia (n=14) than during propofol anaesthesia (n=13) (0.3 vs 1.1 ml kg-1 h-1 [P=0.01] and 2.6 vs 6.0 mmol h-1 [P=0.04], respectively). Urinary potassium excretion was lower during anaesthesia than after, without intergroup difference (2.3 vs 5.7 mmol h-1, P<0.001). Sevoflurane anaesthesia increased plasma renin compared with baseline (138 vs 23 mIU L-1, P<0.001) and propofol anaesthesia (138 vs 27 mIU L-1, P=0.008). Plasma arginine-vasopressin did not change significantly during anaesthesia, but was elevated postoperatively compared with baseline irrespective of anaesthetic (21 vs 12 ng L-1, P=0.02). Sevoflurane caused higher postoperative plasma creatinine than propofol (83 vs 66 mmol L-1, P=0.01). Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin did not change significantly in either group.Conclusions: Sevoflurane anaesthesia reduced urine output and sodium excretion and increased plasma renin compared with propofol anaesthesia. The impact of this on acute kidney injury and fluid resuscitation during surgery warrants further investigation.Clinical Trial Registration: EudraCT: 2017-001646-10; Clinicaltrials.gov: NCT0333680. [ABSTRACT FROM AUTHOR]

Spontaneously hypertensive rats (SHR) display deficiency of epoxyeicosatrienoic acids (EETs). Their possible interaction with renal sympathetic nerves remains unexplored; synthesis of EET-A [disodium (S)-2-(13-(3- pentyl)ureido)-tridec-8(Z)-enamido)succinate], a stable 14,15-EET analog, helps clarify the issue. In anesthetized SHR, untreated or pretreated with EET-A, we assessed early responses of blood pressure (MAP), renal hemodynamics and excretion, and indices of nitric oxide (NO) activity, to bilateral noninvasive renal denervation (DNX). DNX significantly decreased MAP, with or without EET-A pretreatment. Renal perfusion decreased in EET-A treated but not in control rats. After EET-A pretreatment DNX decreased renal excretion of sodium and total solutes, compared to increasing tendency in untreated rats. In EET-A treated but not in untreated SHR denervation reduced the excretion of NO metabolites. Antihypertensive action of EET-A in anesthetized SHR was not clearly dependent on renal nerve activity. On the other hand, DNX unmasked the unexpected effect of EET-A to lower renal perfusion. The mechanism of this novel finding is unclear, as is also the simultaneous post-denervation decrease in renal excretion, again, observed only under EET-A treatment. Possibly, the decrease was secondary to falling MAP and renal perfusion. Increased renal excretion of nitric oxide metabolites under EETs elevation strongly suggests facilitation of NO release; the effect that was observed only with intact renal nerve activity. [ABSTRACT FROM AUTHOR]

Hypertension is a common medical condition; its prevalence increases with age. It is one of the most important risk factors for cardiovascular disease, which is the leading cause of mortality. High salt intake is associated with high blood pressure. The incidence of hypertension is higher in salt-sensitive individuals. Evidence shows that reduced sodium intake lowers blood pressure and can prevent hypertension. Urinary sodium excretion was used as measure of sodium intake, which equals urinary excretion under normal circumstances. The relationship between salt intake and renal ability to excrete sodium has suggested being a major importance for the long-term blood pressure treatment especially in essential hypertension. In the present study there was increased 24 hour sodium excretion in essential hypertensives indicating a high intake of sodium, which may be the cause for hypertension. Patients with high sodium excretion, who are salt sensitive hypertensives will respond to diuretics, when compared to others. The long term reduction in salt intake may significantly reduce the prevalence of hypertension and thereby decrease the associated morbidity and mortality. [ABSTRACT FROM AUTHOR]

The intake of Saccharina japonica (SJ), a widely consumed brown seaweed, has been reported to decrease blood pressure (BP) in hypertensive rats. It has been suggested that this effect is related to an increase in fecal sodium excretion (SE) by alginate (Alg) to the gastrointestinal tract; however, the mechanism is still unclear. This study investigated how different seaweeds with different amounts of Alg suppressed BP increase and enhanced fecal SE in 2-kidney, 1-clip renovascular hypertensive (2K1C) rats given SJ diet. Rats with 2K1C or sham operation were fed a normal-/high-salt diet with some kinds of seaweeds (5.0%, w/w) or SJ extract with different Alg contents for 6 weeks. We measured systolic BP every week and mean arterial pressure at the end, and measured the total and molecular weights of Alg in each seaweed. Then, we evaluated the relationship of the Alg amount in each seaweed with the suppression of BP increase in 2K1C rats. Finally, urinary and fecal SE for 24 h was measured. The intake of SJ, SJ extract, Saccharina ochotensis (SO) blades and SO roots suppressed BP increase in 2K1C rats, but the strength was not proportional to the amounts of Alg contained in the seaweeds. Although SJ intake increased fecal SE in 2K1C rats fed a high-salt diet, the fecal SE was much less than urinary SE. The sodium excretion in feces by Alg in SJ may not be one of the major mechanisms by which SJ intake attenuates hypertension in 2K1C rats. [ABSTRACT FROM AUTHOR]

The measurement of sodium intake may be important for the management of hypertension. Dietary surveys and 24-h urinary collection are often unreliable and/or impractical. We hypothesized that urinary sodium excretion can be accurately estimated through multiple spot urine samples from different days. All enrolled subjects were children of the coauthors of the study. Fifty-two 24-h urinary collections (4 per subject) for measuring sodium excretion and the 297 related urinary samples (1 per voiding) were collected for calculating the urinary sodium/urinary creatinine ratio in 13 children. The mean of 4 measured sodium excretions served as the individual "gold standard". Twenty-four urinary collections were used to generate the equation predicting the mean measured sodium excretion from the mean of 4 urinary sodium/urinary creatinine [= 0.016 × urinary sodium (mmol/L) / urinary creatinine (mmol/L) ratio + 3.3)]; the remaining 28 urinary collections and 153 urinary samples were used for the external validation. All subjects underwent an additional validation procedure involving 12 urinary samples randomly collected on different days 6 months apart. The performance of sodium excretion calculated from a total of over 22,000 possible means of 4 out of all the available urinary samples, randomly taken on different days, was analyzed as to precision (by means of the coefficient of variation) and as to accuracy (by means of the P30). The coefficients of variations of measured vs. calculated sodium excretion were 25.3% vs. 25.8%, and the P30 of calculated sodium excretion was 100%. The excellent performance of calculated sodium excretion was confirmed both by external validation and by samples collected 6 months apart with mean P30s, all between 86 and 100%. Conclusion: In the described experimental conditions, urinary sodium excretion was estimated with equal precision and more accurately (and practically) by the mean of 4 urinary sodium/urinary creatinine ratios from random samples from different days than by a single urinary collection. In real life, with several errors systematically affecting urinary collection, the superiority of calculated sodium excretion is likely to be even greater. What is Known: • The measurement of sodium intake with the current standards of care (dietary survey or 24-h urinary collection) is laborious and can be inaccurate. What is New: • The study provides evidence that sodium intake can be estimated equally precisely, more accurately and more practically with the urinary sodium-to-urinary creatinine ratio from 4 urine samples taken on different days than with a single urinary collection. [ABSTRACT FROM AUTHOR]

Abstract Background Premenopausal women have a lower risk of hypertension compared to age-matched men and postmenopausal women. P2Y2 and P2Y4 purinoceptor can be considered potential contributors to hypertension due to their emerging roles in regulating renal tubular Na+ transport. Activation of these receptors inhibits epithelial Na+ channel activity (ENaC) via a phospholipase C (PLC)-dependent pathway resulting in natriuresis. We recently reported that activation of P2Y2 and P2Y4 receptors in the renal medulla by UTP promotes natriuresis in male and ovariectomized (OVX) rats, but not in ovary-intact females. This led us to hypothesize that ovary-intact females have greater basal renal medullary activity of P2 (P2Y2 and P2Y4) receptors regulating Na+ excretion compared to male and OVX rats. Methods To test our hypothesis, we determined (i) the effect of inhibiting medullary P2 receptors by suramin (750 μg/kg/min) on urinary Na+ excretion in anesthetized male, ovary-intact female, and OVX Sprague Dawley rats, (ii) mRNA expression and protein abundance of P2Y2 and P2Y4 receptors, and (iii) mRNA expression of their downstream effectors (PLC-1δ and ENaCα) in renal inner medullary tissues obtained from these three groups. We also subjected cultured mouse inner medullary collecting duct cells (segment 3, mIMCD3) to different concentrations of 17ß-estradiol (E2, 0, 10, 100, and 1000 nM) to test whether E2 increases mRNA expression of P2Y2 and P2Y4 receptors. Results Acute P2 inhibition attenuated urinary Na+ excretion in ovary-intact females, but not in male or OVX rats. We found that P2Y2 and P2Y4 mRNA expression was higher in the inner medulla from females compared to males or OVX. Inner medullary lysates showed that ovary-intact females have higher P2Y2 receptor protein abundance, compared to males; however, OVX did not eliminate this sex difference. We also found that E2 dose-dependently upregulated P2Y2 and P2Y4 mRNA expression in mIMCD3. Conclusion These data suggest that ovary-intact females have enhanced P2Y2 and P2Y4-dependent regulation of Na+ handling in the renal medulla, compared to male and OVX rats. We speculate that the P2 pathway contributes to facilitated renal Na+ handling in premenopausal females.

Background The aim of this study was to investigate the effect of long-term low salt diet on blood pressure and its underlying mechanisms. Methods Male Sprague-Dawley (SD) rats were divided into normal salt diet group (0.4%) and low salt diet group (0.04%). Blood pressure was measured with the non-invasive tail-cuff method. The contractile response of isolated mesenteric arteries was measured using a small vessel myograph. The effects on renal function of the intrarenal arterial infusion of candesartan (10 μg/kg/min), an angiotensin II receptor type 1 (AT1R) antagonist, were also measured. The expressions of renal AT1R and mesenteric arterial α1A, α1B, and α1D adrenergic receptors were quantified by immunoblotting. Plasma levels of angiotensin II were also measured. Results Systolic blood pressure was significantly increased after 8 weeks of low salt diet. There were no obvious differences in the renal structure between the low and normal salt diet groups. However, the plasma angiotensin II levels and renal AT1R expression were higher in low than normal salt diet group. The intrarenal arterial infusion of candesartan increased urine flow and sodium excretion to a greater extent in the low than normal salt diet group. The expressions of α1A and α1D, but not α1B, adrenergic receptors, and phenylephrine-induced contraction were increased in mesenteric arteries from the low salt, relative to the normal salt diet group. Conclusion Activation of the renin-angiotensin and sympathetic nervous systems may be involved in the pathogenesis of long-term low salt diet-induced hypertension.

Background and Objectives: The pathophysiological mechanisms linking weight loss to blood pressure (BP) reduction are not completely understood. The objective of this study was to compare the effect of weight loss after Roux-en-Y gastric bypass (RYGB) on BP, renin-angiotensin-aldosterone system (RAAS), and urinary electrolytes excretion to those of dietary advice. Methods: This was a case-control prospective study including obese patients referred for RYGB (cases) and obese receiving diet advice only (controls). Ambulatory BP, plasma renin activity (PRA), plasma aldosterone concentration (PAC), and urinary electrolytes were measured before (M0) and after intervention (M3: 3 months and M12: 12 months). Results: Twenty-five patients were included in the RYGB group and twelve patients in the control group. After 12 months, weight loss (-42 ± 11.5 vs -12.3 ± 6.3 kg in the control group, p=0.001) and decrease in PAC were more pronounced in the RYGB group (-34 ± 76 vs +14 ± 45 pg/ml in the control group, p=0.002). There was no difference in PRA between both groups (-0.08 ± 1.68 vs 0.01 ± 0.37 ng/ml/h, p=0.31). Sodium excretion was more marked in the RYGB group after 3 months only (-89 ± 14.9 vs -9.9 ± 27.9 mmol/day, p=0.009). The decrease in SBP was similar between both groups (-6.9 ± 9.9 vs -7.1 ± 11.9 mmHg in the control group, p=0.96). Conclusions: Bariatric-induced weight loss induces a progressive decrease in PAC independently of PRA and sodium excretion. Whether this decrease in PAC affects target organ damage in the long term remains to be determined. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT02218112. [ABSTRACT FROM AUTHOR]

Background We have previously shown that high salt stimulates the expression of miR-429 in the renal medulla, which induces mRNA decay of HIF prolyl-hydroxylase 2 (PHD2), an enzyme to promote the degradation of hypoxia-inducible factor (HIF)-1α, and increases the HIF-1α-mediated activation of antihypertensive genes in the renal medulla, consequently promoting extra sodium excretion. Our preliminary results showed that high salt-induced increase of miR-429 was not observed in Dahl S rats. This present study determined whether correction of this impairment in miR-429 would reduce PHD2 levels, increase antihypertensive gene expression in the renal medulla and attenuate salt-sensitive hypertension in Dahl S rats. Methods Lentiviruses encoding rat miR-429 were transfected into the renal medulla in uninephrectomized Dahl S rats. Sodium excretion and blood pressure were then measured. Results Transduction of lentiviruses expressing miR-429 into the renal medulla increased miR-429 levels, decreased PHD2 levels, and upregulated HIF-1α target gene NOS-2, which restored the adaptive mechanism to increase the antihypertensive gene after high-salt intake in Dahl S rats. Functionally, overexpression of miR-429 transgene in the renal medulla significantly improved pressure natriuretic response, enhanced urinary sodium excretion, and reduced sodium retention upon extra sodium loading, and consequently, attenuated the salt-sensitive hypertension in Dahl S rats. Conclusions Our results suggest that the impaired miR-429-mediated PHD2 inhibition in response to high salt in the renal medulla may represent a novel mechanism for salt-sensitive hypertension in Dahl S rats and that correction of this impairment in miR-429 pathway could be a therapeutic approach for salt-sensitive hypertension. [ABSTRACT FROM AUTHOR]

Vitamin E is a fat-soluble component that has an antioxidant effect in the body, and there are many research reports on the physiological functionality of ex-tocopherol. In recent years, however, it has been reported that y-tocopherol also has various physiological actions such as a diuretic action and a urinary sodium excretion promoting action. In this study, in order to confirm a urinary sodium excretion promoting effect of y-tocopherol in long-term dietary intake, we prepared canola oil containing high y-tocopherol, and investigated urine volume, urinary sodium excretion, and blood biochemical test value in high-salt diet (5-8% NaCl diet) Sprague -Dawley rats administered continuously high y-tocopherol oil for 28 days. As a result, on day 15, the urine volume of high y-tocopherol oil administration group increased significantly (p く〇・05) as compared with the control group. On day 15 and 22, the urine sodium excretion of high y-tocopherol oil administration group seemed increased significantiy (p <0.05) as compared with the control group, however, food intake was also significantly increased (p <0.05) compared to the control, resulting in a correlation between sodium intake and excretion. Therefore, in this study, we could not observe the urinary sodium excretion promoting effect of administered continuously high y-tocopherol oil, but an increased urine output. In addition, as a result of blood biochemical test after the end of administered continuously, the blood glucose level of high y-tocopherol oil administration group was significantiy (p <0.01) lower than that of the control. Since the blood glucose level decreased and the difference of tocopherol content observed in the liver, it may be considered the possibility that the increase of y-tocopherol in the blood affected the glycolipid metabolism due to the continuous intake of y-tocopherol. [ABSTRACT FROM AUTHOR]

The activity of the Epithelial Na+ Channel (ENaC) in renal principal cells (PC) fine-tunes sodium excretion and consequently, affects blood pressure. The Gs-adenylyl cyclase-cAMP signal transduction pathway is believed to play a central role in the normal control of ENaC activity in PCs. The current study quantifies the importance of this signaling pathway to the regulation of ENaC activity in vivo using a knock-in mouse that has conditional expression of Gs-DREADD (designer receptors exclusively activated by designer drugs; GsD) in renal PCs. The GsD mouse also contains a cAMP response element-luciferase reporter transgene for non-invasive bioluminescence monitoring of cAMP signaling. Clozapine N-oxide (CNO) was used to selectively and temporally stimulate GsD. Treatment with CNO significantly increased luciferase bioluminescence in the kidneys of PC-specific GsD but not control mice. CNO also significantly increased the activity of ENaC in principal cells in PC-specific GsD mice compared to untreated knock-in mice and CNO treated littermate controls. The cell permeable cAMP analog, 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate, significantly increased the activity and expression in the plasma membrane of recombinant ENaC expressed in CHO and COS-7 cells, respectively. Treatment of PC-specific GsD mice with CNO rapidly and significantly decreased urinary Na+ excretion compared to untreated PC-specific GsD mice and treated littermate controls. This decrease in Na+ excretion in response to CNO in PC-specific GsD mice was similar in magnitude and timing as that induced by the selective vasopressin receptor 2 agonist, desmopressin, in wild type mice. These findings demonstrate for the first time that targeted activation of Gs signaling exclusively in PCs is sufficient to increase ENaC activity and decrease dependent urinary Na+ excretion in live animals. [ABSTRACT FROM AUTHOR]

Background and ObjectivesThe pathophysiological mechanisms linking weight loss to blood pressure (BP) reduction are not completely understood. The objective of this study was to compare the effect of weight loss after Roux-en-Y gastric bypass (RYGB) on BP, renin-angiotensin-aldosterone system (RAAS), and urinary electrolytes excretion to those of dietary advice.MethodsThis was a case-control prospective study including obese patients referred for RYGB (cases) and obese receiving diet advice only (controls). Ambulatory BP, plasma renin activity (PRA), plasma aldosterone concentration (PAC), and urinary electrolytes were measured before (M0) and after intervention (M3: 3 months and M12: 12 months).ResultsTwenty-five patients were included in the RYGB group and twelve patients in the control group. After 12 months, weight loss (-42 ± 11.5 vs -12.3 ± 6.3 kg in the control group, p=0.001) and decrease in PAC were more pronounced in the RYGB group (-34 ± 76 vs +14 ± 45 pg/ml in the control group, p=0.002). There was no difference in PRA between both groups (-0.08 ± 1.68 vs 0.01 ± 0.37 ng/ml/h, p=0.31). Sodium excretion was more marked in the RYGB group after 3 months only (-89 ± 14.9 vs -9.9 ± 27.9 mmol/day, p=0.009). The decrease in SBP was similar between both groups (-6.9 ± 9.9 vs -7.1 ± 11.9 mmHg in the control group, p=0.96).ConclusionsBariatric-induced weight loss induces a progressive decrease in PAC independently of PRA and sodium excretion. Whether this decrease in PAC affects target organ damage in the long term remains to be determined.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT02218112.

Objective: This study aims to investigate the relationship between dietary salt intake and residual renal function in peritoneal dialysis (PD) patients.Methods: The daily salt intake of the patients was calculated based on a 3 day dietary record. Sixty-two patients were divided into three groups: 33 patients in the low salt intake group (salt intake

The activity of the Epithelial Na+ Channel (ENaC) in renal principal cells (PC) fine-tunes sodium excretion and consequently, affects blood pressure. The Gs-adenylyl cyclase-cAMP signal transduction pathway is believed to play a central role in the normal control of ENaC activity in PCs. The current study quantifies the importance of this signaling pathway to the regulation of ENaC activity in vivo using a knock-in mouse that has conditional expression of Gs-DREADD (designer receptors exclusively activated by designer drugs; GsD) in renal PCs. The GsD mouse also contains a cAMP response element-luciferase reporter transgene for non-invasive bioluminescence monitoring of cAMP signaling. Clozapine N-oxide (CNO) was used to selectively and temporally stimulate GsD. Treatment with CNO significantly increased luciferase bioluminescence in the kidneys of PC-specific GsD but not control mice. CNO also significantly increased the activity of ENaC in principal cells in PC-specific GsD mice compared to untreated knock-in mice and CNO treated littermate controls. The cell permeable cAMP analog, 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate, significantly increased the activity and expression in the plasma membrane of recombinant ENaC expressed in CHO and COS-7 cells, respectively. Treatment of PC-specific GsD mice with CNO rapidly and significantly decreased urinary Na+ excretion compared to untreated PC-specific GsD mice and treated littermate controls. This decrease in Na+ excretion in response to CNO in PC-specific GsD mice was similar in magnitude and timing as that induced by the selective vasopressin receptor 2 agonist, desmopressin, in wild type mice. These findings demonstrate for the first time that targeted activation of Gs signaling exclusively in PCs is sufficient to increase ENaC activity and decrease dependent urinary Na+ excretion in live animals.

Introduction: Hypertension predisposes to atrial fibrillation (AF) – a major risk factor for ischaemic stroke. Since a high dietary salt consumption is associated with hypertension, we investigated the association between urinary sodium excretion as a marker for dietary sodium intake and risk of new‐onset AF in community‐dwelling adults. Method: The UK Biobank includes 40‐ to 69‐year‐old British residents recruited 2006–2010. Participants were divided into sex‐specific quintiles according to 24‐hour sodium excretion estimated based on spot samples with the Kawasaki equation. We excluded participants with AF at baseline. Cox regression adjusted for cardiovascular risk factors was used to assess associations with risk of AF, using the third quintile as reference. Results: A total of 257 545 women and 215 535 men were included. During up to 10 years' follow‐up, 2221 women and 3751 men were diagnosed with AF. There was a tendency for an increased risk of AF in the lowest and highest quintiles of estimated daily salt intake in both women and men. In the fully adjusted model, significant associations were seen amongst men in the lowest and highest quintiles of sodium excretion (hazard ratio, HRQv1, 1.20; 95% CI, 1.08–1.32, P < 0.001, and HRQv5 1.15, 95% CI, 1.03–1.27, P = 0.011). Conclusion: We found evidence for a U‐shaped association between estimated daily salt intake and AF risk amongst men. A suggestive J‐shaped association in women was not statistically confirmed, but analyses were likely underpowered. Our results suggest that above a certain physiological minimum level progressively higher salt intake is associated with increasing risk of AF. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells (MSC) improve renal function and renovascular hypertension in the 2-kidney 1-clip model (2K-1C). While MSC play an immunomodulatory role, induce neoangiogenesis, and reduce fibrosis, they do not correct sodium loss by the contra­lateral kidney. Objectives: We investigated the tubular function of both stenotic and contralateral kidneys and the effect of MSC treatment by evaluating diuresis, natriuresis, and the expression of the main water and sodium transporters. Method: Adult Wistar rats were allocated into four groups: control (CT), CT+MSC, 2K-1C, and 2K-1C+MSC. MSC (2 × 105) were infused through the tail vein 3 and 5 weeks after clipping. Systolic blood pressure (SBP) was monitored weekly by plethysmography. Six weeks after clipping, 24-hour urine and blood samples were collected for biochemical analysis. Gene expression of the Na/H exchanger-3, epithelial sodium channel, Na/K-ATPase, Na/K/2Cl cotransporter, and aquaporins 1 and 2 (AQP1 and AQP2) were analyzed by RT-PCR. Intrarenal distribution of AQP1 and AQP2 was analyzed by immunohistochemistry. Results: In hypertensive 2K-1C animals, MSC prevented additional increases in BP. AQP1, but not AQP2, was suppressed in the contralateral kidney, resulting in significant increase in urinary flow rate and sodium excretion. Gene expressions of sodium transporters were similar in both kidneys, suggesting that the high perfusing pressure in the contralateral kidney was responsible for increased natriuresis. Contralateral hypertensive kidney showed signs of renal deterioration with lower GFR in spite of normal RPF levels. Conclusions: MSC treatment improved renal function and enhanced the ability of the contralateral kidney to excrete sodium through a tubular independent mechanism contributing to reduce SBP.

Background : Several epidemiologic studies have suggested that the urine sodium excretion (USE) can be estimated in lieu of performing 24-hour urine collection. However, this method has not been verified in patients with chronic kidney disease (CKD) or in an interventional study. The purpose of this study was to evaluate the usefulness of estimating USE in a prospective low-salt diet education cohort (ESPECIAL). Methods : A new formula was developed on the basis of morning fasting urine samples from 228 CKD patients in the ESPECIAL cohort. This formula was compared to the previous four formulas in the prediction of 24-hour USE after treatment with olmesartan and low-salt diet education. Results : Most previously reported formulas had low predictability of the measured USE based on the ESPECIAL cohort. Only the Tanaka formula showed a small but significant bias (9.8 mEq/day, P < 0.05) with a low correlation (r = 0.34). In contrast, a new formula showed improved bias (−0.1 mEq/day) and correlation (r = 0.569) at baseline. This formula demonstrated no significant bias (−1.2 mEq/day) with the same correlation (r = 0.571) after 8 weeks of treatment with olmesartan. Intensive low-salt diet education elicited a significant decrease in the measured USE. However, none of the formulas predicted this change in the measured urine sodium after diet adjustment. Conclusion : We developed a more reliable formula for estimating the USE in CKD patients. Although estimating USE is applicable in an interventional study, it may be unsuitable for estimating the change of individual sodium intake in a low-salt intervention study.

Abstract Background Previous studies have reported an association between dietary sodium intake and overweight/central obesity. However, dietary survey methods were prone to underestimate sodium intake. Therefore, this study investigated the associations of calculated 24-h urinary sodium excretion, an index of dietary sodium intake, with various obesity parameters including body mass index (BMI) and waist circumference (WC) in a population with a relatively high sodium intake. Methods A total of 16,250 adults (aged ≥19 years) and 1476 adolescents (aged 10-18 years), with available information on spot urine sodium levels and anthropometric measurements from the Korea National Health and Nutrition Examination Survey (KNHANES) were included in this study. We calculated 24-h urine sodium excretion levels from spot urine sodium levels using the Tanaka formula. Results In adults, those with high sodium excretion levels (≥ 3200 mg) showed increased odds of overweight and central obesity compared to those with low urinary sodium excretion level (

Angiotensin II (Ang II) type-2 receptors (AT2R) are expressed in the adult kidney, prominently in renal proximal tubule cells (RPTCs), and play an important role in opposing renal sodium (Na+) retention induced by Ang II stimulation of Ang II type-1 receptor (AT1R). Natriuresis induced by AT1R blockade is due at least in part to AT2R activation and whole body deletion of AT2Rs reduces the natriuretic response to increased blood pressure (BP). The major endogenous AT2R agonist mediating the natriuretic response is Ang III, the Ang II heptapeptide metabolite generated by aminopeptidase A, and the principal nephron site mediating inhibition of Na+ reabsorption by the AT2R is the renal proximal tubule (RPT). AT2Rs induce natriuresis via a bradykinin, nitric oxide and cyclic GMP (cGMP) signaling cascade. Recent studies demonstrated a key role for protein phosphatase 2A (PP2A) in the AT2R-mediated natriuretic response upstream of cGMP. By inducing natriuresis, AT2Rs lower BP in the Ang II-infusion model of hypertension. PP2A activation and the natriuretic response to AT2R stimulation are defective in spontaneously hypertensive rats, a model of primary hypertension in humans. AT2R agonists are candidates for proximal tubule natriuretic agents in Na+ and fluid retention disorders.

Timing of food intake has become a critical factor in determining overall cardiometabolic health. We hypothesized that timing of food intake entrains circadian rhythms of blood pressure (BP) and renal excretion in mice. Male C57BL/6J mice were fed ad libitum or reverse feeding (RF) where food was available at all times of day or only available during the 12-h lights-on period, respectively. Mice eating ad libitum had a significantly higher mean arterial pressure (MAP) during lights-off compared to lights-on (113 ± 2 mmHg vs 100 ± 2 mmHg, respectively; P < 0.0001); however, RF for 6 days inverted the diurnal rhythm of MAP (99 ± 3 vs 110 ± 3 mmHg, respectively; P < 0.0001). In contrast to MAP, diurnal rhythms of urine volume and sodium excretion remained intact after RF. Male Bmal1 knockout mice (Bmal1KO) underwent the same feeding protocol. As previously reported, Bmal1KO mice did not exhibit a diurnal MAP rhythm during ad libitum feeding (95 ± 1 mmHg vs 92 ± 3 mmHg, lights-off vs lights-on; P > 0.05); however, RF induced a diurnal rhythm of MAP (79 ± 3 mmHg vs 95 ± 2 mmHg, lights-off vs lights-on phase; P < 0.01). Transgenic PERIOD2::LUCIFERASE knock-in mice were used to assess the rhythm of the clock protein PERIOD2 in ex vivo tissue cultures. The timing of the PER2::LUC rhythm in the renal cortex and suprachiasmatic nucleus was not affected by RF; however, RF induced significant phase shifts in the liver, renal inner medulla, and adrenal gland. In conclusion, the timing of food intake controls BP rhythms in mice independent of Bmal1, urine volume, or sodium excretion. Graphical Abstract [ABSTRACT FROM AUTHOR]

Background The novel estrogen receptor, G‐protein–coupled estrogen receptor (GPER), is responsible for rapid estrogen signaling. GPER activation elicits cardiovascular and nephroprotective effects against salt‐induced complications, yet there is no direct evidence for GPER control of renal Na+ handling. We hypothesized that GPER activation in the renal medulla facilitates Na+ excretion. Methods and Results Herein, we show that infusion of the GPER agonist, G1, to the renal medulla increased Na+ excretion in female Sprague Dawley rats, but not male rats. We found that GPER mRNA expression and protein abundance were markedly higher in outer medullary tissues from females relative to males. Blockade of GPER in the renal medulla attenuated Na+ excretion in females. Given that medullary endothelin 1 is a well‐established natriuretic factor that is regulated by sex and sex steroids, we hypothesized that GPER activation promotes natriuresis via an endothelin 1–dependent pathway. To test this mechanism, we determined the effect of medullary infusion of G1 after blockade of endothelin receptors. Dual endothelin receptor subtype A and endothelin receptor subtype B antagonism attenuated G1‐induced natriuresis in females. Unlike males, female mice with genetic deletion of GPER had reduced endothelin 1, endothelin receptor subtype A, and endothelin receptor subtype B mRNA expression compared with wild‐type controls. More important, we found that systemic GPER activation ameliorates the increase in mean arterial pressure induced by ovariectomy. Conclusions Our data uncover a novel role for renal medullary GPER in promoting Na+ excretion via an endothelin 1–dependent pathway in female rats, but not in males. These results highlight GPER as a potential therapeutic target for salt‐sensitive hypertension in postmenopausal women.

It is important to grasp a patient’s daily sodium intake in the management of chronic kidney disease, as sodium intake is widely recommended at 6 g/day or less. There are multiple equations widely known for estimating the daily sodium excretion from a spot urine sample, but these are aimed at healthy people. There are few reports that validate equations in patients with chronic kidney disease. The purpose of this study is to evaluate whether the amount of measured daily sodium excretion from a sample collected for 24-h urine (24HU) is equal to that of using an equation from a spot urine sample (SU) in patients with chronic kidney disease. One hundred sixty-two patients with chronic kidney disease from Kanagawa Prefecture Shiomidai Hospital, Japan and the Jikei University Kashiwa Hospital, Japan participated in the study. Daily sodium excretion was measured from 24HU and compared with it from SU by using the formula according to Tanaka et al. Sodium excretion by 24HU was 2744 mg/day and estimating daily sodium excretion from SU was 3315 mg/day. The coefficient of determination was 0.17 (p

INTRODUCTION: Sympathetic and Renin-Angiotensin-Aldosterone systems play crucial roles in blood pressure response to increased salt intake. This study investigated the effects of angiotensin receptor blocker (ARB) and sympathetic excitation on the responses of blood pressure (BP) and peripheral vascular resistance (PVR) in salt loaded normotensive (NT) and hypertensive (HT) Nigerian subjects. Methods: 16 NT and 14 HT participants, that were age-matched [39.9,1.3 vs 44.1,2.1yrs (P=0.10)], underwent 5 days each of oral administration of 200 mmol NaCl, and 200 mmol NaCl + 50 mg Losartan, preceded by a baseline control condition. BP and PVR responses to 30% Maximum Voluntary Contraction (MVC) of handgrip (HG) for one minute were determined at baseline, after salt load and after salt + losartan. Data were presented as Mean , SEM, and analyzed with Two-way ANOVA and paired t-test, with P=0.05 accepted as significant. Results: BP and PVR were significantly increased by HG at baseline, after salt load and after salt + losartan in NT and HT. Salt load augmented the HG-induced SBP (P = 0.04) and MABP responses (P = 0.02) in HT. While losartan attenuated the HG-induced SBP response (P = 0.007) and DBP response (P = 0.003) in HT and NT respectively after salt + losartan. HG-induced PVR response was significantly accentuated after salt load in HT (P = 0.005), but it was not significant in NT(P=0.38). Conclusion: the implication of our finding is that angiotensin II receptor blockade possibly attenuates salt-induced sympathetic nerve excitation in black hypertensive patients.

Background: High sodium intake is a major public health concern. Sodium consumption pattern of West Indian population has never been reported before. Objectives: The cross-sectional study assessed sodium intake pattern by considering all possible dietary sources and spot urine sodium estimation among sedentary healthy adults of productive age group (35–55 years). Materials and Methods: Twenty-four-h dietary recall (3 alternative days in a week), food frequency assessment, weighing of table, and cooking salt (n = 218) were performed. Spot urine samples were collected for subset (n = 33) to quantify sodium excretion. Flame photometer “CL 361” was used for food sodium quantification. Results: Men had higher sodium intake than women (3.9 ± 0.4 vs. 3.8 ± 0.4 g/day). Significantly higher sodium intake among men was from processed ready to eat foods (0.8 ± 0.3 vs. 0.6 ± 0.1, P < 0.05) and among women was from cooking and table salt (2.6 ± 0.3 vs. 2.8 ± 0.3, P < 0.001). Lowest quartile (

This study investigated the effect of mineral-balanced deep-sea water (DSW) on kidney health using an animal model of kidney injury due to a high-sodium diet. High magnesium/low sodium (HMLS) and high magnesium/high calcium (HMHC) DSW samples with different mineral contents were prepared. Sprague–Dawley rats were fed an 8% sodium chloride (NaCl) diet for four weeks to induce kidney injury, and each group was supplied with purified water or mineral water. Kidney injury was observed in the NaCl group according to increased kidney injury markers and malondialdehydes, providing evidence of oxidative stress. However, the kidney injury was repaired by the intake of mineral-balanced DSW. It was confirmed that the HMLS and HMHC groups showed improved Na+ excretion through the urine. Kidney injury markers in urine decreased and upregulation of low-density lipoprotein receptor-related protein2 mRNA expression was observed in the HMLS and HMHC groups. In addition, superoxide dismutase activity was increased in the HMHC groups. The gene expression patterns of the RNA sequencing were similar between the CON and HMLS groups. These results suggest that DSW has beneficial effects on kidney health due to the balanced magnesium and calcium levels in models of kidney injury caused by excessive sodium intake.

Background: It is a matter of debate whether sodium and potassium intake are associated with heart disease. Further, the mechanisms underlying associations of sodium and potassium intake with cardiac events, if any, are not fully understood.Objectives: We examined cross-sectional associations of 24-h urinary sodium excretion (UNaE) and potassium excretion (UKE), as estimates of their intakes, with high-sensitivity cardiac troponins T (hs-cTnT) and I (hs-cTnI), and N-terminal pro-B-type natriuretic peptide (NT-proBNP), which are markers of cardiomyocyte injury and cardiac dysfunction.Methods: We included 2961 participants from the population-based Maastricht Study (mean ± SD age 59.8 ± 8.2 y, 51.9% men), who completed the baseline survey between November 2010 and September 2013. Associations were examined with restricted cubic spline linear regression analyses and ordinary linear regression analyses, adjusted for demographics, lifestyle, and cardiovascular disease (CVD) risk factors.Results: Median [IQR] 24-h UNaE and UKE were 3.7 [2.8-4.7] g/24 h and 3.0 [2.4-3.6] g/24 h, respectively. After adjustment for potential confounders, 24-h UNaE was not associated with hs-cTnT, hs-cTnI, and NT-proBNP concentrations. In contrast, after adjustment for potential confounders, lower 24-h UKE was nonlinearly associated with higher hs-cTnT and NT-proBNP. For example, as compared with the third/median quintile of 24-h UKE (range: 2.8-3.2 g/24 h), participants in the first quintile (range: 0.5-2.3 g/24 h) had 1.05 (95% CI: 0.99, 1.11) times higher hs-cTnT and 1.14 (95% CI: 1.03, 1.26) times higher NT-proBNP. Associations were similar after further adjustment for estimated glomerular filtration rate, albuminuria, blood pressure, and serum potassium.Conclusions: Twenty-four-hour UNaE was not associated with the studied cardiac biomarkers. In contrast, lower 24-h UKE was nonlinearly associated with higher hs-cTnT and NT-proBNP. This finding supports recommendations to increase potassium intake in the general population. In addition, it suggests that cardiac dysfunction and/or cardiomyocyte injury may underlie previously reported associations of lower potassium intake with CVD mortality. [ABSTRACT FROM AUTHOR]

In Victoria, Australia, a statewide salt reduction partnership was launched in 2015. The aim was to measure Na intake, food sources of Na (level of processing, purchase origin) and discretionary salt use in a cross-section of Victorian adults prior to a salt reduction initiative. In 2016/2017, participants completed a 24-h urine collection (n 338) and a subsample completed a 24-h dietary recall (n 142). Participants were aged 41·2 (sd 13·9) years, and 56 % were females. Mean 24-h urinary excretion was 138 (95 % CI 127, 149) mmol/d for Na. Salt equivalent was 8·1 (95 % CI 7·4, 8·7) g/d, equating to about 8·9 (95 % CI 8·1, 9·6) g/d after 10 % adjustment for non-urinary losses. Mean 24-h intake estimated by diet recall was 118 (95 % CI 103, 133) mmol/d for Na (salt 6·9 (95 % CI 6·0, 7·8 g/d)). Leading dietary sources of Na were cereal-based mixed dishes (12 %), English muffins, flat/savoury/sweet breads (9 %), regular breads/rolls (9 %), gravies and savoury sauces (7 %) and processed meats (7 %). Over one-third (38 %) of Na consumed was derived from discretionary foods. Half of all Na consumed came from ultra-processed foods. Dietary Na derived from foods was obtained from retail stores (51 %), restaurants and fast-food/takeaway outlets (28 %) and fresh food markets (9 %). One-third (32 %) of participants reported adding salt at the table and 61 % added salt whilst cooking. This study revealed that salt intake was above recommended levels with diverse sources of intake. Results from this study suggest a multi-faceted salt reduction strategy focusing on the retail sector, and food reformulation would most likely benefit Victorians and has been used to inform the ongoing statewide salt reduction initiative. [ABSTRACT FROM AUTHOR]

Brian M Waldman,1,2 Robert A Augustyniak,1–3 Haiping Chen,1,2 Noreen F Rossi1,2,4 1Department of Internal Medicine, 2Department of Physiology, Wayne State University School of Medicine, Detroit, MI, 3Department of Biomedical Sciences, Edward Via College of Osteopathic Medicine-Carolinas, Spartanburg, SC, 4Department of Internal Medicine, John D Dingell Veterans Administration Medical Center, Detroit, MI, USA Abstract: Spontaneous dynamic exercise promotes sympathoinhibition and decreases arterial pressure in two-kidney, one-clip (2K-1C) hypertensive rats. Renal sympathetic nerves stimulate renin secretion and increase renal tubular sodium reabsorption. We hypothesized that daily voluntary wheel running exercise by 2K-1C rats will decrease mean arterial pressure (MAP), plasma angiotensin II (Ang II), and aldosterone as well as normalize urinary sodium and potassium excretion independent of changes in glomerular filtration rate (GFR). Five-week-old male Sprague Dawley rats underwent sham clipping (Sham) or right renal artery clipping (2K-1C). Rats were randomized to standard caging (SED) or cages with running wheels (EX). After 12 weeks, rats were assigned to either collection of aortic blood for measurement of Ang II and aldosterone or assessment of inulin clearances and excretory function. Running distances were comparable in both EX groups. MAP was lower in 2K-1C EX vs 2K-1C SED rats (P

Background The aim of this study was to investigate the effect of long-term low salt diet on blood pressure and its underlying mechanisms. Methods Male Sprague-Dawley (SD) rats were divided into normal salt diet group (0.4%) and low salt diet group (0.04%). Blood pressure was measured with the non-invasive tail-cuff method. The contractile response of isolated mesenteric arteries was measured using a small vessel myograph. The effects on renal function of the intrarenal arterial infusion of candesartan (10 μg/kg/min), an angiotensin II receptor type 1 (AT1R) antagonist, were also measured. The expressions of renal AT1R and mesenteric arterial α1A, α1B, and α1D adrenergic receptors were quantified by immunoblotting. Plasma levels of angiotensin II were also measured. Results Systolic blood pressure was significantly increased after 8 weeks of low salt diet. There were no obvious differences in the renal structure between the low and normal salt diet groups. However, the plasma angiotensin II levels and renal AT1R expression were higher in low than normal salt diet group. The intrarenal arterial infusion of candesartan increased urine flow and sodium excretion to a greater extent in the low than normal salt diet group. The expressions of α1A and α1D, but not α1B, adrenergic receptors, and phenylephrine-induced contraction were increased in mesenteric arteries from the low salt, relative to the normal salt diet group. Conclusion Activation of the renin-angiotensin and sympathetic nervous systems may be involved in the pathogenesis of long-term low salt diet-induced hypertension. [ABSTRACT FROM AUTHOR]