Dietary sodium induces a redistribution of the tubular metabolic workload.

KEY POINTS: Body Na+ content is tightly controlled by regulated urinary Na+ excretion. The intrarenal mechanisms mediating adaptation to variations in dietary Na+ intake are incompletely characterized. We confirmed and expanded observations in mice that variations in dietary Na+ intake do not alter the glomerular filtration rate but alter the total and cell-surface expression of major Na+ transporters all along the kidney tubule. Low dietary Na+ intake increased Na+ reabsorption in the proximal tubule and decreased it in more distal kidney tubule segments. High dietary Na+ intake decreased Na+ reabsorption in the proximal tubule and increased it in distal segments with lower energetic efficiency. The abundance of apical transporters and Na+ delivery are the main determinants of Na+ reabsorption along the kidney tubule. Tubular O2 consumption and the efficiency of sodium reabsorption are dependent on sodium diet. ABSTRACT: Na+ excretion by the kidney varies according to dietary Na+ intake. We undertook a systematic study of the effects of dietary salt intake on glomerular filtration rate (GFR) and tubular Na+ reabsorption. We examined the renal adaptive response in mice subjected to 7 days of a low sodium diet (LSD) containing 0.01% Na+ , a normal sodium diet (NSD) containing 0.18% Na+ and a moderately high sodium diet (HSD) containing 1.25% Na+ . As expected, LSD did not alter measured GFR and increased the abundance of total and cell-surface NHE3, NKCC2, NCC, α-ENaC and cleaved γ-ENaC compared to NSD. Mathematical modelling predicted that tubular Na+ reabsorption increased in the proximal tubule but decreased in the distal nephron because of diminished Na+ delivery. This prediction was confirmed by the natriuretic response to diuretics targeting the thick ascending limb, the distal convoluted tubule or the collecting system. On the other hand, HSD did not alter measured GFR but decreased the abundance of the aforementioned transporters compared to NSD. Mathematical modelling predicted that tubular Na+ reabsorption decreased in the proximal tubule but increased in distal segments with lower transport efficiency with respect to O2 consumption. This prediction was confirmed by the natriuretic response to diuretics. The activity of the metabolic sensor adenosine monophosphate-activated protein kinase (AMPK) was related to the changes in tubular Na+ reabsorption. Our data show that fractional Na+ reabsorption is distributed differently according to dietary Na+ intake and induces changes in tubular O2 consumption and sodium transport efficiency.

The Validity of Predictive Equations to Estimate 24-Hour Sodium Excretion: The MESA and CARDIA Urinary Sodium Study.

We examined the population distribution of urinary sodium concentrations and the validity of existing equations predicting 24-hour sodium excretion from a single spot urine sample among older adults with and without hypertension. In 2013, 24-hour urine collections were obtained from 554 participants in the Multi-Ethnic Study of Atherosclerosis and the Coronary Artery Risk Development in Young Adults study, who were aged 45-79 years and of whom 56% were female, 58% were African American, and 54% had hypertension, in Chicago, Illinois. One-third provided a second 24-hour collection. Four timed (overnight, morning, afternoon, and evening) spot urine specimens and the 24-hour collection were analyzed for sodium and creatinine concentrations. Mean 24-hour sodium excretion was 3,926 (standard deviation (SD), 1,623) mg for white men, 2,480 (SD, 1,079) mg for white women, 3,454 (SD, 1,651) mg for African-American men, and 3,397 (SD, 1,641) mg for African-American women, and did not differ significantly by hypertensive status. Mean bias (difference) in predicting 24-hour sodium excretion from the timed spot urine specimens ranged from -182 (95% confidence interval: -285, -79) to 1,090 (95% confidence interval: 966, 1,213) mg/day overall. Although the Tanaka equation using the evening specimen produced the least bias overall, no single equation worked well across subgroups of sex and race/ethnicity. A single spot urine sample is not a valid indicator of individual sodium intake. New equations are needed to accurately estimate 24-hour sodium excretion for older adults.

Validation of spot urine in predicting 24-h sodium excretion at the individual level.

Background: Evidence for the effect of dietary sodium intake on the risk of cardiovascular disease has been controversial. One of the main explanations for the conflicting results lies in the great variability associated with measurement methods for sodium intake. Spot urine collection is a convenient method commonly used for sodium estimation, but its validity for predicting 24-h urinary sodium excretion at the individual level has not been well evaluated among the general population.Objective: The aim of this study was to evaluate the validity of the Kawasaki, the International Cooperative Study on Salt, Other Factors, and Blood Pressure (INTERSALT), and the Tanaka formulas in predicting 24-h urinary sodium excretion by using spot urine samples in Chinese adults.Design: We analyzed the relative and absolute differences and misclassification at the individual level from 3 commonly used methods for estimating sodium intake among 141 Chinese community residents.Results: The mean measured 24-h sodium excretion was 220.8 mmol/d. The median (95% CIs) differences between measured sodium and those estimated from the Kawasaki, INTERSALT, and Tanaka methods were 6.4 mmol/d (-17.5, 36.8 mmol/d), -67.3 mmol/d (-96.5, -46.9 mmol/d), and -42.9 mmol/d (-59.1, -24.8 mmol/d), respectively. The proportions of relative differences >40% with the Kawasaki, INTERSALT, and Tanaka methods were 31.2%, 41.1%, and 22.0%, respectively; and the absolute difference for the 3 methods was >51.3 mmol/d (3 g salt) in approximately half of the participants. The misclassification rate was 63.1% for the Kawasaki method, 78.7% for the INTERSALT method, and 66.0% for the Tanaka method at the individual level.Conclusion: The results from our study do not support the use of spot urine to estimate 24-h urinary sodium excretion at the individual level because of its poor performance with respect to misclassification. This trial was registered at www.chictr.org.cn as ChiCTR-IOR-16010278.

La ingesta elevada de sodio disminuye la respuesta antiproteinúrica del bloqueo del eje renina-angiotensina-aldosterona en el trasplante renal / A high sodium intake reduces antiproteinuric response to renin-angiotensin-aldosterone system blockade in kidney transplant recipients

Antecedentes: La proteinuria postrasplante renal se asocia a una disminución en la supervivencia del injerto y del paciente. Para reducir la proteinuria y mejorar el pronóstico renal se recomienda asociar fármacos bloqueantes del sistema renina-angiotensina-aldosterona (RAA). Aunque en los pacientes no trasplantados se ha demostrado que la dieta rica en sal reduce el efecto antiproteinúrico de los IECA y ARA-II, este efecto no se ha estudiado en los trasplantados renales. Objetivo: Valorar la relación entre la ingesta de sodio y el efecto antiproteinúrico de los IECA/ARA-II en los trasplantados renales. Métodos: Seleccionamos a 103 trasplantados tratados con IECA/ARA-II más de 6 meses por proteinuria>1g/día. La proteinuria se analizó al inicio del tratamiento y a los 6 meses. La ingesta de sal se estimó con el cociente urinario sodio/creatinina (uNa/Cr). Resultados: En 46 pacientes (44,7%) la proteinuria disminuyó<1g/día. Un uNa/Cr elevado se relaciona con un menor descenso de la proteinuria (r=−0,251; p=0,011). El porcentaje de reducción de la proteinuria fue significativamente menor en los pacientes en el tercil más alto de uNa/Cr [63,9% (RIC 47,1%); 60,1% (RIC 55,4%); 38,9% (RIC 85,5%); p=0,047]. Un uNa/Cr elevado se relaciona de forma independiente (OR 2,406 por 100 mEq/g; IC 95%: 1,008-5,745; p=0,048) a una respuesta antiproteinúrica<50% tras el bloqueo del eje RAA. Conclusiones: En los trasplantados renales con proteinuria tratados con IECA/ARA-II una ingesta elevada de sal se asocia con un menor descenso de la proteinuria (AU)

Background: Post-transplant proteinuria is associated with lower graft and patient survival. Renin-angiotensin-aldosterone system blockers are used to reduce proteinuria and improve renal outcome. Although it is known that a high salt intake blunts the antiproteinuric effect of ACEI and ARB drugs in non-transplant patients, this effect has not been studied in kidney transplant recipients. Objective: To analyse the relationship between sodium intake and the antiproteinuric effect of ACEI/ARB drugs in kidney transplant recipients. Methods: We selected 103 kidney transplant recipients receiving ACEI/ARB drugs for more than 6 months due to proteinuria>1 g/day. Proteinuria was analysed at baseline and at 6 months after starting ACEI/ARB treatment. Salt intake was estimated by urinary sodium to creatinine ratio (uNa/Cr). Results: Proteinuria fell to less than 1g/day in 46 patients (44.7%). High uNa/Cr was associated with a smaller proteinuria decrease (r=−0.251, P=.011). The percentage proteinuria reduction was significantly lower in patients in the highest uNa/Cr tertile [63.9% (IQR 47.1%), 60.1% (IQR 55.4%), 38.9% (IQR 85.5%),P=.047]. High uNa/Cr independently relates (OR 2.406 per 100 mEq/g, 95% CI: 1.008-5.745, P=.048) to an antiproteinuric response <50% after renin-angiotensin-aldosterone system blockade. Conclusions: A high salt intake results in a smaller proteinuria decrease in kidney transplant recipients with proteinuria treated with ACEI/ARB drugs (AU)

Genetic and molecular aspects of hypertension.

Until recently, significant advances in our understanding of the mechanisms of blood pressure regulation arose from studies of monogenic forms of hypertension and hypotension, which identified rare variants that primarily alter renal salt handling. Genome-wide association and exome sequencing studies over the past 6 years have resulted in an unparalleled burst of discovery in the genetics of blood pressure regulation and hypertension. More importantly, genome-wide association studies, while expanding the list of common genetic variants associated with blood pressure and hypertension, are also uncovering novel pathways of blood pressure regulation that augur a new era of novel drug development, repurposing, and stratification in the management of hypertension. In this review, we describe the current state of the art of the genetic and molecular basis of blood pressure and hypertension.

Sodium intake and cardiovascular health.

Sodium is an essential nutrient. Increasing sodium intake is associated with increasing blood pressure, whereas low sodium intake results in increased renin and aldosterone levels. Randomized controlled trials have reported reductions in blood pressure with reductions in sodium intake, to levels of sodium intake <1.5 g/d, and form the evidentiary basis for current population-wide guidelines recommending low sodium intake. Although low sodium intake (<2.0 g/d) has been achieved in short-term feeding clinical trials, sustained low sodium intake has not been achieved by any of the longer term clinical trials (>6-month duration). It is assumed that the blood pressure-lowering effects of reducing sodium intake to low levels will result in large reductions in cardiovascular disease globally. However, current evidence from prospective cohort studies suggests a J-shaped association between sodium intake and cardiovascular events, based on studies from >300 000 people, and suggests that the lowest risk of cardiovascular events and death occurs in populations consuming an average sodium intake range (3-5 g/d). The increased risk of cardiovascular events associated with higher sodium intake (>5 g/d) is most prominent in those with hypertension. A major deficit in the field is the absence of large randomized controlled trials to provide definitive evidence on optimal sodium intake for preventing cardiovascular events. Pending such trials, current evidence would suggest a recommendation for moderate sodium intake in the general population (3-5 g/d), with targeting the lower end of the moderate range among those with hypertension.

Rhesus monkey model for concurrent analyses of in vivo selectivity, pharmacokinetics and pharmacodynamics of aldosterone synthase inhibitors.

INTRODUCTION: In vivo profiles of aldosterone synthase inhibitors (ASIs) have been investigated utilizing various rodent models. Due to lack of CYP17 activity, rodents produce corticosterone rather than cortisol as that of humans, which raised concern to their effectiveness in translational pharmacological characterization of ASI. METHODS: A rhesus monkey model that combines a low sodium diet with adrenocorticotropin (ACTH) treatment was developed. Plasma concentrations of steroid metabolites associated with reactions catalyzed by CYP11B2 and CYP11B1 were measured concurrently by a UPLC/MS method. RESULTS: Plasma concentration of aldosterone in regular diet fed rhesus monkeys was low at 109pg/mL. Aldosterone concentrations were increased to 252pg/mL when animals were maintained on a low sodium diet for 3weeks, and to 300pg/mL with ACTH treatment at 0.3mg/kg. The combination of low sodium diet with ACTH treatment further increased plasma concentration of aldosterone to 730pg/mL and other steroid metabolites at various levels. Intravenous administration of ASI, fadrozole (0.001-1mg/kg) or LCI699 (0.003-3mg/kg), led to dose-dependent reductions in aldosterone and 18-hydroxycorticosterone, increases in 11-deoxycorticosterone and 11-deoxycortisol, and bell-shaped changes in cortisol and corticosterone. In vivo selectivity of CYP11B2/CYP11B1 for fadrazole was 26-fold and LCI-699 was 27-fold, which was consistent with relative selectivity using in vitro values from recombinant cells transfected with rhesus monkey CYP11B2 and CYP11B1. DISCUSSION: This model enables concurrent characterization of pharmacokinetics, pharmacodynamics and selectivity of CYP11B2 over CYP11B1 inhibition in the same animal. It may be used as a translational model for pharmacological characterization of ASI.

Clock genes in hypertension: novel insights from rodent models.

The circadian clock plays an integral role in the regulation of physiological processes, including the regulation of blood pressure. However, deregulation of the clock can lead to pathophysiological states including hypertension. Recent work has implicated the circadian clock genes in the regulation of processes in the heart, kidney, vasculature, and the metabolic organs, which are all critical in the regulation of the blood pressure. The goal of this review is to provide an introduction and general overview into the role of circadian clock genes in the regulation of blood pressure with a focus on their deregulation in the etiology of hypertension. This review will focus on the core circadian clock genes CLOCK, BMAL1, Per, and Cry.

Sodium intake may promote weight gain; results of the FANPE study in a representative sample of the adult Spanish population / La ingesta de sodio puede favorecer el incremento de peso; resultados del estudio FANPE realizado en una muestra representativa de adultos españoles

Introduction: Recent studies have indicated that diets rich in sodium may predispose to the development of obesity, either directly, or be associated with the consumption of foods that promote weight gain. Objective: The aims of this study were to analyze the association between urinary sodium and the presence of excess of weight. Additionally, the study investigated the relationships between salt intake and dietary habits, as a high salt intake may be associated with inadequate eating habits and a high incidence of obesity. Methods: This study involved 418 adults (196 men and 222 women) aged 18 to 60 years old. Weight, height and waist circumference were measured, and we calculated, BMI and waist/height ratio. Dietary intake was estimated using a «24 h recalls», for two consecutive days, and sodium content was determined from 24 h urine sample. Results: The 34.4% of the population had overweight and 13.6% had obesity. A positive association was seen between BMI and urinary sodium concentration. Urine sodium values were also positively associated with others adiposity indicators such as waist circumference and waist/height ratio. Body weight, BMI, waist circumference, and waist/height ratio were higher in the group of individuals with a urinary sodium excretion ≥ 154 mmol/l (Percentile 50) (P50). Additionally, individuals placed in this group presented a higher caloric intake and total food intake, in particular, more meat, processed food and snacks. Adjusting by energy intake, a higher sodium intake was a risk factor of being overweight or obese (OR = 1.0041, IC 95% 1.0015-1.0067, p < 0.01). Conclusions: Salt intake was associated with obesity; since people with higher sodium intake consumed more energy and presented worse eating habits. Additionally, sodium intake itself appears to be related to obesity (AU)

Introducción: Estudios recientes, han señalado que las dietas ricas en sodio podrían predisponer a la aparición de obesidad, ya sea de forma directa, o por estar asociadas con el consumo de alimentos que favorecen el aumento de peso. Objetivo: El objeto de este estudio fue analizar la asociación entre sodio urinario y presencia de sobrepeso y obesidad, en una muestra representativa de adultos españoles, así como conocer si el mayor consumo de sal, se asocia con unos peores hábitos alimentarios y con una mayor ingesta de alimentos, que puedan predisponer a la aparición de la misma. Métodos: Se ha estudiado un grupo de 418 adultos (196 hombres y 222 mujeres) de 18 a 60 años de edad. Se recogieron datos de peso, talla, circunferencia de cintura y se calculó, a partir de ellos, el IMC y el índice cintura/talla. Con el fin de conocer el consumo de alimentos, se aplicó un «Recuerdo de 24 horas» durante dos días consecutivos y se determinó el sodio en orina de 24 horas. Resultados: Un 34,4% de la población presentó sobrepeso y un 13,6% obesidad. Se observó una asociación positiva entre el IMC y la excreción urinaria de sodio. Los valores de sodio en orina también se relacionaron de forma directa con otros parámetros indicadores de adiposidad, como la circunferencia de la cintura o la relación cintura/talla. Tanto el peso, como el IMC, la circunferencia de la cintura y la relación cintura/talla, fueron mayores en el grupo con una excreción urinaria de sodio ≥ 154 mmol/l (Percentil 50) (P50). Además, las personas con una mayor eliminación urinaria de sodio presentaron una mayor ingesta calórica y un mayor consumo de alimentos totales y, en concreto, de carnes, precocinados y aperitivos. Tras ajustar por la ingesta de energía, la mayor ingesta de sodio resultó ser un factor de riesgo de tener un IMC más alto (OR = 1.0041, IC 95% 1.0015-1.0067, p < 0,01). Conclusiones: La ingesta de sal estuvo asociada con la presencia de obesidad, ya que las personas con una mayor ingesta de sodio ingirieron más energía y presentaron peores hábitos alimentarios. Sin embargo, la ingesta de sodio por sí misma, también parece estar relacionada con el padecimiento de obesidad (AU)

The impact of iron content in a diet high in fat, fructose, and salt on metabolic state and mineral status of rats

The purpose of the study was to assess the influence of dietary iron content on lipid and carbohydrate metabolism and on zinc and copper status in rats fed with a diet high in fat, fructose, and salt. Wistar rats were fed with diets high in fat, fructose, and salt, containing differing amounts of iron, namely, deficit, normal, and high levels. After 6 weeks, the animals were weighed and killed. The liver, heart, and pancreas were collected, as were blood samples. The total cholesterol, triglycerides, fasting glucose, and insulin levels in the serum were measured. The iron, zinc, and copper concentrations in tissues and serum were determined. It was found that in rats fed with the iron-deficit diet, cholesterol and glucose profiles improved. Both deficit and excess iron in the diet decreased insulin concentration in rats and disturbed iron, zinc, and copper status. High-iron level in the diet decreased the relative mass of the pancreas. In conclusion, the decrease in serum insulin concentration observed in rats fed with the modified diet high in iron was associated with iron and copper status disorders, and also, with a relatively diminished pancreas mass. A deficit of iron in the diet improved lipid and carbohydrate metabolism in rats

Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression.

Hypertension and chronic kidney disease (CKD) are complex traits representing major global health problems. Multiple genome-wide association studies have identified common variants in the promoter of the UMOD gene, which encodes uromodulin, the major protein secreted in normal urine, that cause independent susceptibility to CKD and hypertension. Despite compelling genetic evidence for the association between UMOD risk variants and disease susceptibility in the general population, the underlying biological mechanism is not understood. Here, we demonstrate that UMOD risk variants increased UMOD expression in vitro and in vivo. Uromodulin overexpression in transgenic mice led to salt-sensitive hypertension and to the presence of age-dependent renal lesions similar to those observed in elderly individuals homozygous for UMOD promoter risk variants. The link between uromodulin and hypertension is due to activation of the renal sodium cotransporter NKCC2. We demonstrated the relevance of this mechanism in humans by showing that pharmacological inhibition of NKCC2 was more effective in lowering blood pressure in hypertensive patients who are homozygous for UMOD promoter risk variants than in other hypertensive patients. Our findings link genetic susceptibility to hypertension and CKD to the level of uromodulin expression and uromodulin's effect on salt reabsorption in the kidney. These findings point to uromodulin as a therapeutic target for lowering blood pressure and preserving renal function.

Dietary sodium intake modulates renal excretory responses to intrarenal angiotensin (1-7) administration in anesthetized rats.

Angiotensin II at the kidney regulates renal hemodynamic and excretory function, but the actions of an alternative metabolite, angiotensin (1-7), are less clear. This study investigated how manipulation of dietary sodium intake influenced the renal hemodynamic and excretory responses to intrarenal administration of angiotensin (1-7). Renal interstitial infusion of angiotensin (1-7) in anesthetized rats fed a normal salt intake had minimal effects on glomerular filtration rate but caused dose-related increases in urine flow and absolute and fractional sodium excretions ranging from 150 to 200%. In rats maintained for 2 wk on a low-sodium diet angiotensin (1-7) increased glomerular filtration rate by some 45%, but the diuretic and natriuretic responses were enhanced compared with those in rats on a normal sodium intake. By contrast, renal interstitial infusion of angiotensin (1-7) in rats maintained on a high-sodium intake had no effect on glomerular filtration rate, whereas the diuresis and natriuresis was markedly attenuated compared with those in rats fed either a normal or low-sodium diet. Plasma renin and angiotensin (1-7) were highest in the rats on the low-sodium diet and depressed in the rats on a high-sodium diet. These findings demonstrate that the renal hemodynamic and excretory responses to locally administered angiotensin (1-7) is dependent on the level of sodium intake and indirectly on the degree of activation of the renin-angiotensin system. The exact way in which angiotensin (1-7) exerts its effects may be dependent on the prevailing levels of angiotensin II and its receptor expression.

Importance and benefits of dietary sodium restriction in the management of chronic kidney disease patients: experience from a single Chinese center.

AIM: Several studies have suggested that sodium intake may affect blood pressure (BP), proteinuria, and intrarenal transforming growth factor-ß1 (TGF-ß1) production in patients and animal models with chronic kidney disease (CKD). The Chinese population has a high prevalence of CKD and is well known for consuming salty foods. This study will investigate the role of dietary sodium intake on BP control among non-dialysis Chinese CKD patients. METHODS: A cross-sectional study was carried out in a cohort of 176 non-dialysis hypertensive CKD patients to investigate their sodium intake and its effect on BP control by measuring 24-h urine sodium excretion (24-h UNa). A total of 20 patients with immunoglobulin A nephropathy (IgAN) participated in a 7-day sodium restriction study (100 mmol/day). Their changes in BP, proteinuria, and urinary TGF-ß1 excretion were subsequently analyzed. Another 23 IgAN patients without salt restriction were included as controls. RESULTS: The average 24-h UNa of the study cohort was 149.0 ± 66.4 mmol/day. Only 31.8% patients had a 24-h UNa less than 100 mmol/day. The OR for each 17 mmol increment in 24-h UNa (salt 1 g/day) for BP > 130/80 mmHg was 1.26 (95% CI 1.10-1.44, P = 0.001). The sodium restriction group achieved significantly more reduction in SBP (-11.1 mmHg vs. -5.0 mmHg, P = 0.022), DBP (-9.4 mmHg vs. -2.1 mmHg, P = 0.009), and urine protein excretion [-465 (-855 to -340) mg/day vs. -150 (-570 to 40) mg/day, P = 0.024]. A positive correlation was observed between the change of 24-h UNa and the change of SBP (r = 0.450, P = 0.047) in the sodium restriction group. The change of 24-h UNa was also correlated with the 24-h TGF-ß1 excretion (r = 0.558, P = 0.011) in these patients. CONCLUSION: Dietary sodium intake restriction should be monitored and intensified in the treatment of Chinese CKD patients.

Aldosterone in uremia - beyond blood pressure.

Aldosterone was in the past considered only as a prohypertensinogenic agent. It has recently become clear that apart from the classical endocrine action, i.e. causing blood pressure elevation as a result of salt retention, aldosterone has numerous blood-pressure-independent actions on nonepithelial tissue. Under conditions of high salt concentration, aldosterone is injurious to the kidney, heart and vasculature. Of particular interest are recent observations that aldosterone is a permissive factor for the effect of minor increases in plasma sodium concentration on endothelial cell dysfunction. Despite surprising effects of aldosterone blockade on blood pressure of anuric dialysis patients, the potential role of mineralocorticoid receptor blockade in dialysis patients is currently unclear and requires controlled investigation to define the risk of potential hazards, specifically hyperkalemia.

Hyperosmolar sodium chloride, p38 mitogen activated protein and cytokine-mediated inflammation.

Although there is increasing clinical evidence that high salt intake contributes to cardiovascular events and deaths seemingly independent of hypertension, the molecular mechanism for increased atherogenesis remains unclear. Vessel wall inflammation secondary to proinflammatory cytokines is one mechanism for atherogenesis. The role of mitogen activated protein kinase (MAPK) p38 in cytokine production such as IL-1, TNF-alpha, and IL-8 are well established. The link between inflammation and salt intake likely includes p38 MAPK as hyperosmolar sodium chloride triggers phosphorylation of p38 MAPK and stimulates gene expression and synthesis of proinflammatory cytokines. Hence a possible link of high salt intake, inflammation, and atherogenesis may be one molecular mechanism for the association of high salt intake and cardiovascular events.

Salt sensitivity of children with low birth weight.

Compromised intrauterine fetal growth leading to low birth weight (<2500 g) is associated with adulthood renal and cardiovascular disease. The aim of this study was to assess the effect of salt intake on blood pressure (salt sensitivity) in children with low birth weight. White children (n=50; mean age: 11.3+/-2.1 years) born with low (n=35) or normal (n=15) birth weight and being either small or appropriate for gestational age (n=25 in each group) were investigated. The glomerular filtration rate was calculated using the Schwartz formula, and renal size was measured by ultrasound. Salt sensitivity was assigned if mean 24-hour blood pressure increased by >or=3 mm Hg on a high-salt diet as compared with a controlled-salt diet. Baseline office blood pressure was higher and glomerular filtration rate lower in children born with low birth weight as compared with children born at term with appropriate weight (P<0.05). Salt sensitivity was present in 37% and 47% of all of the low birth weight and small for gestational age children, respectively, higher even than healthy young adults from the same region. Kidney length and volume (both P<0.0001) were reduced in low birth weight children. Salt sensitivity inversely correlated with kidney length (r(2)=0.31; P=0.005) but not with glomerular filtration rate. We conclude that a reduced renal mass in growth-restricted children poses a risk for a lower renal function and for increased salt sensitivity. Whether the changes in renal growth are causative or are the consequence of the same abnormal "fetal programming" awaits clarification.

Epithelial Na+ channel activation and processing in mice lacking SGK1.

Amiloride-sensitive Na(+) channel activity was examined in the cortical collecting ducts of a mouse line (SGK1(-/-)) deficient in the serum- and glucocorticoid-dependent protein kinase SGK1. This activity was correlated with changes in renal Na handling and in the maturation of epithelial Na(+) channel (ENaC) protein. Neither SGK1(-/-) mice nor paired SGK1(+/+) animals expressed detectable channel activity, measured as amiloride-sensitive whole-cell current (I(Na)), under control conditions with standard chow. Administration of aldosterone (0.5 microg/h via osmotic minipump for 7 days) increased I(Na) to a similar extent in SGK1(+/+) (378 +/- 61 pA/cell at -100 mV) and in SGK1(-/-) (350 +/- 57 pA/cell) animals. However, the maturation of ENaC, assessed as the ratio of cleaved to full-length forms of gamma-ENaC, was more pronounced in SGK(+/+) mice. The SGK1(-/-) animals exhibited a salt-wasting phenotype when kept on a low-Na diet for up to 2 days, losing significantly more Na in the urine than wild-type mice. Under these conditions, I(Na) was enhanced more in SGK1(-/-) (94 +/- 14 pA/cell) than in SGK(+/+) (23 +/- 5 pA/cell) genotypes. Despite the larger currents, the ratio of cleaved to full-length gamma-ENaC was lower in the knockout animals. The mice also expressed a smaller amount of Na(+)-Cl(-) cotransporter protein under Na-depleted conditions. These results indicated that SGK1 is essential for optimal processing of ENaC but is not required for activation of the channel by aldosterone.

Kir4.1/Kir5.1 channel forms the major K+ channel in the basolateral membrane of mouse renal collecting duct principal cells.

K(+) channels in the basolateral membrane of mouse cortical collecting duct (CCD) principal cells were identified with patch-clamp technique, real-time PCR, and immunohistochemistry. In cell-attached membrane patches, three K(+) channels with conductances of approximately 75, 40, and 20 pS were observed, but the K(+) channel with the intermediate conductance (40 pS) predominated. In inside-out membrane patches exposed to an Mg(2+)-free medium, the current-voltage relationship of the intermediate-conductance channel was linear with a conductance of 38 pS. Addition of 1.3 mM internal Mg(2+) had no influence on the inward conductance (G(in) = 35 pS) but reduced outward conductance (G(out)) to 13 pS, yielding a G(in)/G(out) of 3.2. The polycation spermine (6 x 10(-7) M) reduced its activity on inside-out membrane patches by 50% at a clamp potential of 60 mV. Channel activity was also dependent on intracellular pH (pH(i)): a sigmoid relationship between pH(i) and channel normalized current (NP(o)) was observed with a pK of 7.24 and a Hill coefficient of 1.7. By real-time PCR on CCD extracts, inwardly rectifying K(+) (Kir)4.1 and Kir5.1, but not Kir4.2, mRNAs were detected. Kir4.1 and Kir5.1 proteins cellularly colocalized with aquaporin 2 (AQP2), a specific marker of CCD principal cells, while AQP2-negative cells (i.e., intercalated cells) showed no staining. Dietary K(+) had no influence on the properties of the intermediate-conductance channel, but a Na(+)-depleted diet increased its open probability by approximately 25%. We conclude that the Kir4.1/Kir5.1 channel is a major component of the K(+) conductance in the basolateral membrane of mouse CCD principal cells.