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Proper renal blood flow (RBF) and glomerular filtration rate (GFR) are critical for maintaining normal blood pressure, kidney function and water and electrolyte homeostasis. The renal microvasculature expresses a multitude of receptors mediating vasodilation and vasoconstriction, which can influence glomerular blood flow and capillary pressure. Despite this, RBF and GFR remain quite stable when arterial pressure fluctuates because of the autoregulatory mechanism. ATP and adenosine participate in autoregulatory control of RBF and GFR via activation of two different purinoceptor families (P1 and P2). Purinoceptors are widely expressed in renal microvasculature and tubules. Emerging data show altered purinoceptor signaling in hypertension-associated kidney injury, diabetic nephropathy, sepsis, ischemia-reperfusion induced acute kidney injury and polycystic kidney disease. In this brief review, we highlight recent studies and new insights on purinoceptors regulating renal microvascular function and renal hemodynamics. We also address the mechanisms underlying renal microvascular injury and impaired renal autoregulation, focusing on purinoceptor signaling and hypertension-induced renal microvascular dysfunction. Interested readers are directed to several excellent and comprehensive reviews that recently covered the topics of renal autoregulation, and nucleotides in kidney function under physiological and pathophysiological conditions (Inscho 2009, Navar et al. 2008, Carlstrom et al. 2015, Vallon et al. 2020). [ABSTRACT FROM AUTHOR]

Enhanced activation of the endothelial mineralocorticoid receptor contributes to the development of arterial stiffness, which is an independent predictor of cardiovascular disease. Previously, we showed that enhanced endothelium mineralocorticoid receptor signaling in female mice prompts expression and translocation of the α-subunit of the epithelial sodium channel to the endothelial cell (EC) surface (EnNaC) inducing vascular fibrosis and stiffness. Further, amiloride, an epithelial sodium channel antagonist, inhibits vascular fibrosis, remodeling, and stiffness induced by feeding a Western diet high in saturated fat and refined carbohydrates. However, how this occurs remains unknown. Thereby, we hypothesized that endothelial cell-specific EnNaC activation is necessary for aldosterone-mediated endothelium stiffness. To address this notion, EnNaC α-subunit knockout (EnNaC-/-) and wild-type littermate female mice were administrated aldosterone (250 µg/kg per day) via osmotic minipumps for 3 weeks beginning at 25 to 28 weeks of age. In isolated mouse endothelial cells, inward sodium currents were significantly reduced in amiloride controls, as well as in EnNaC-/-. Likewise, aldosterone-induced endothelium stiffness was increased and endothelium-dependent relaxation less in EnNaC-/- versus wild-type. Further, EnNaC-/- mice exhibited attenuated responses to aldosterone infusion, including aortic endoplasmic reticulum stress, endothelium nitric oxide synthase activation, endothelium permeability, expression of proinflammatory cytokines, oxidative stress, and aortic collagen 1 deposition, supporting the notion that αEnNaC subunit activation contributes to these vascular responses. [ABSTRACT FROM AUTHOR]

Increasing evidence shows that antigen-presenting cells (APCs) are involved in the development of inflammation associated to hypertension. However, the potential role of APCs in the modulation of renal sodium transport has not been addressed. We hypothesized that APCs participate in renal sodium transport and, thus, development of high blood pressure in response to angiotensin II plus a high-salt diet. Using transgenic mice that allow the ablation of CD11chigh APCs, we studied renal sodium transport, the intrarenal renin-angiotensin system components, blood pressure, and cardiac/renal tissue damage in response to angiotensin II plus a high-salt diet. Strikingly, we found that APCs are required for the development of hypertension and that the ablation/restitution of APCs produces rapid changes in the blood pressure in mice with angiotensin II plus a high-salt diet. Moreover, APCs were necessary for the induction of intrarenal renin-angiotensin system components and affected the modulation of natriuresis and tubular sodium transporters. Consistent with the prevention of hypertension, the ablation of APCs also prevented cardiac hypertrophy and the induction of several indicators of renal and cardiac damage. Thus, our findings indicate a prominent role of APCs as modulators of blood pressure by mechanisms including renal sodium handling, with kinetics that suggest the involvement of tubular cell functions in addition to the modulation of inflammation and adaptive immune response. [ABSTRACT FROM AUTHOR]

Liddle syndrome is considered a rare Mendelian hypertension. We have previously described 3 reportedly unrelated families, native of an Italian area around the Strait of Messina, carrying the same mutation (βP617L) of the epithelial sodium channel. The aims of our study were (1) to evaluate whether a close genomic relationship exists between the 3 families through the analysis of mitochondrial DNA and Y chromosome; and (2) to quantify the genomic relatedness between the patients with Liddle syndrome belonging to the 3 families and assess the hypothesis of a mutation shared through identity by descent. HVRI (the hypervariable region I) of the mitochondrial DNA genome and the Y chromosome short tandem repeats profiles were analyzed in individuals of the 3 families. Genotyping 542 585 genome-wide single nucleotide polymorphisms was performed in all the patients with Liddle syndrome of the 3 families and some of their relatives. A panel of 780 healthy Italian adult samples typed for the same set of markers was used as controls. espite different lineages between the 3 families based on the analysis of mitochondrial DNA and Y chromosome, the 3 probands and their 6 affected relatives share the same ≈5 Mbp long haplotype which encompasses the mutant allele. Using an approach based on coalescent theory, we estimate that the 3 families inherited the mutant allele from a common ancestor ≈13 generations ago and that such an ancestor may have left ≈20 carriers alive today. The prevalence of Liddle syndrome in the region of origin of the 3 families may be much higher than that estimated worldwide. [ABSTRACT FROM AUTHOR]

Epithelial sodium channel (ENaC) has been localized within many organs of various species, including the uterus of mice, rats, and humans. Additionally, ENaC expression within the rodent uterus was differentially influenced by 17β-estradiol (E2) and progesterone (P4), and has been proposed to be the major mechanism regulating uterine fluid absorption and secretion. In the equine, ENaC has been observed in the trachea, hooves, and endometrium; however, the potential relationship between E2, P4, and ENaC in the mare endometrium has yet to be elucidated. The aim of this study was to investigate possible interactions between E2, P4, and ENaC from cycling mares using immunohistochemistry (IHC). Estrus was synchronized for all mares (n = 13) by daily administration of oral altrenogest (ALT) for 15 consecutive days. On the last day of ALT treatment, all mares received 5 mg of dinoprost IM. Following synchronization, all mares were teased daily with a stallion. Transrectal ultrasonography (US) for observation of ovarian activity and day of ovulation (OV; d0) were completed every other day until OV. On d10, US, blood collection via jugular venipuncture, and a uterine biopsy sample were collected. Biopsy samples were fixed to later complete ENaC evaluation by IHC. A uterine biopsysample and blood collection had also been similarly collected and processed for each mare during estrus when she simultaneously had a ≥ 30mm Graafian follicle present and was displaying estrual behaviors. For statistical comparison, a paired t -test was applied. Mares averaged an estrus duration of 4.85 ± 1.86 d. Plasma E2 was 2.27 ± 0.45 pg/mL on d10 and 3.58 ± 0.48 pg/mL on estrus sample day. Plasma P4 concentration was significantly higher (P < 0.01) on d10 when compared with estrus sample day (8.53 ± 1.17 ng/mL vs 0.04 ± 0.02 ng/mL, respectively). The percentage of positively stained ENaC cells was significantly higher (P < 0.01) on d10 when compared with estrus sample day (81.27 ± 3.19% vs 58.84 ± 3.23%). In conclusion, our findings indicate that sex steroids, specifically P4, may regulate ENaC within the mare endometrium, with ENaC being increased during diestrus and decreased during estrus. Collectively, the changes of ENaC concentrations during the estrous cycle might impact the critically sensitive fluid environment within the mare uterus. [ABSTRACT FROM AUTHOR]

Objectives The mechanisms leading to hypertension associated with hyperuricemia are still unclear. The activity of the distal nephron epithelial sodium channel (ENaC) is an important determinant of sodium balance and blood pressure. Our aim was to investigate whether the effect of hyperuricemia on blood pressure is related to ENaC activation. Methods A hyperuricemic model was induced in rats by 2% oxonic acid and 6 mg/dl uric acid (UA). The hyperuricemic rats were co-treated with either 10 mg/kg/d benzbromarone (Ben) or 1 mg/kg/d amiloride (Ami). Blood pressure was monitored using a tail-cuff, and blood, urine, and kidney samples were taken. Western blotting and immunohistochemical staining were performed to determine the expressions of ENaC subunits and components of the ENaC Regulatory Complex (ERC) in kidney tissue or mCCD cells. Results Serum uric acid (SUA) was increased 2.5–3.5 times above normal in hyperuricemic rats after 3 weeks and remained at these high levels until 6 weeks. The in vivo rise in SUA was followed by elevated blood pressure, renal tubulointerstitial injury, and increased expressions of ENaC subunits, SGK1, and GILZ1, which were prevented by Ben treatment. The decrease in urinary Na + excretion in hyperuricemic rats was blunted by Ami. UA induced the expression of all three ENaC subunits, SGK1, and GILZ1, and increased Na + transport in mCCD cells. Phosphorylation of ERK was significantly decreased in both UA-treated mCCD cells and hyperuricemic rat kidney; this effect was prevented by Ben co-treatment. Conclusion Our findings suggest that elevated serum uric acid could induce hypertension by activation of ENaC and regulation of ERC expression. [ABSTRACT FROM AUTHOR]

Excessive salt intake can induce a variety of diseases, such as hypertension, cardiovascular disease, kidney disease and so on，it is also one of the factors promoting bone resorption. The mechanism of osteoporosis-induced exacerbations of high salt diet is not well-defined. In this study, we used ovariectomized 6-month-old Sprague Dawley rats to construct a high bone turnover model, and then administrated with high sodium chloride diet (2.0% w/w NaCl, 8.0% w/w NaCl) for 12 weeks to observe the effect of high salt diet on bone metabolism. The results showed that high salt diet could lead to the destruction of bone microstructure, promote the excretion of urinary calcium and phosphorus and accelerate the bone turnover, as well as cause the pathologic structural abnormalities in renal tubular. At the same time, it was accompanied by the up-regulated expression of the epithelial sodium channel (ENaCα), voltage-gated chloride channels (ClC)− 3 and the down-regulated expression of Na-Cl cotransporter (NCC), sodium calcium exchanger (NCX1) in femoral tissue and renal tubules. These findings confirm that high salt diet can destroy the microstructure of bone by increasing bone resorption and affect some ion channels of bone tissue and renal tubule in ovariectomized rats. • High salt diet exacerbates bone loss in ovariectomized rat. • High salt diet impairs bone microstructure in ovariectomized rat. • High salt diet affects the expression of the ion channels in bone tissue. [ABSTRACT FROM AUTHOR]

Aldosterone plays an essential role in the maintenance of fluid and electrolyte homeostasis in the distal nephron. Monogenic forms of mineralocorticoid hypertension result from genetic defects leading to excessive production of aldosterone (or other mineralocorticoids) from the adrenal cortex or to illegitimate mineralocorticoid effects in the kidney. They are characterized in the majority of cases by early onset, severe or resistant hypertension and associated with suppressed renin levels. Depending on their causes, these diseases are distinguished at the clinical and biochemical level and differently affect aldosterone levels and kalemia. The diagnosis is confirmed by genetic testing, which allows in many cases targeted treatment to prevent severe cardiovascular consequences of high blood pressure or aldosterone excess. In this review we describe the different forms of inherited mineralocorticoid hypertension, providing an overview of their clinical and biochemical features, their underlying genetic defects and specific therapeutic options. [ABSTRACT FROM AUTHOR]

In conditions with albuminuria, plasminogen is aberrantly filtered across the glomerular barrier and activated along the tubular system to plasmin. In the collecting duct, plasmin activates epithelial sodium channels (ENaC) proteolytically. Hyperactivity of ENaC could link microalbuminuria/proteinuria to resistant hypertension. Amiloride, an ENaC inhibitor, inhibits urokinase–type plasminogen activator. We hypothesized that amiloride (1) reduces blood pressure (BP); (2) attenuates plasminogen–to–plasmin activation; and (3) inhibits urine urokinase–type plasminogen activator in patients with resistant hypertension and type 2 diabetes mellitus (T2DM).In an open–label, non–randomized, 8–week intervention study, a cohort (n = 80) of patients with resistant hypertension and T2DM were included. Amiloride (5 mg/d) was added to previous triple antihypertensive treatment (including a diuretic and an inhibitor of the renin–angiotensin–aldosterone system) and increased to 10 mg if BP control was not achieved at 4 weeks. Complete dataset for urine analysis was available in 60 patients. Systolic and diastolic BP measured by ambulatory BP monitoring and office monitoring were significantly reduced. Average daytime BP was reduced by 6.3/3.0 mm Hg. Seven of 80 cases (9%) discontinued amiloride due to hyperkalemia >5.5 mol/L, the most frequent adverse event. Urinary plasmin(ogen) and albumin excretions were significantly reduced after amiloride treatment ( P < .0001). Urokinase activity was detectable in macroalbuminuric urine, with a tendency toward reduction in activity after amiloride treatment. Amiloride lowers BP, urine plasminogen excretion and activation, and albumin/creatinine ratio, and is a relevant add–on medication for the treatment of resistant hypertension in patients with T2DM and microalbuminuria. [ABSTRACT FROM AUTHOR]

An rs3890011 variant of CYP4A11, which is in linkage disequilibrium with the loss-of-function variant rs1126742, is associated with hypertension in humans. In mice, Cyp4a deficiency results in salt-sensitive hypertension through activation of ENaC. We tested the hypothesis that the rs3890011 variant is associated with blood pressure response to drugs acting via the ENaC pathway. African Americans with volume-dependent, resistant hypertension were randomized to treatment with placebo, spironolactone, amiloride, or combination. Blood pressure responses were analyzed by CYP4A11 genotypes. Rs3890011 (GG:GC:CC = 20:35:28) and rs1126742 (TT:TC:CC = 45:31:7) were in linkage disequilibrium (D' = 1, r = 0.561). Expected small number of rs1126742 CC homozygotes precluded analysis of the effect of this genotype on treatment responses. Spironolactone reduced blood pressure in rs3890011 GG and GC individuals, but not in CC homozygotes (P = .002), whereas amiloride reduced blood pressure similarly in all rs3890011 genotypes. The antihypertensive effects of spironolactone and amiloride were comparable in GG and GC participants, but only amiloride reduced pressure in CC homozygotes (-6.3 ± 7.3/-3.2 ± 4.0 vs. +6.8 ± 7.9/+4.8 ± 8.6 mm Hg, P < .01/<.05). The aldosterone response to spironolactone was also blunted in the CC genotype. In individuals homozygous for the CYP4A11 rs3890011 C allele, blood pressure is resistant to mineralocorticoid receptor antagonism, but sensitive to ENaC inhibition, consistent with ENaC activation. Studies in a larger population are needed to replicate these findings. [ABSTRACT FROM AUTHOR]

Summary: The apical membrane epithelial Na+ channel subunit (ENaC) in series with the basolateral Na+/K+-adenosine triphosphatase mediates collecting duct Na+ reabsorption. Aldosterone induces αENaC gene transcription, which appears to be rate limiting for ENaC activity in this segment. Although this response has long been assumed to be solely the result of liganded nuclear hormone receptors trans-activating αENaC, epigenetic controls of basal and aldosterone-induced transcription of αENaC in the collecting duct recently were described. These epigenetic pathways involve dynamic nuclear repressor complexes targeted to specific subregions of the αENaC promoter and consisting of the histone methyltransferase disrupter of telomeric silencing (Dot)1a together with the transcriptional factor Af9 or the nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase Sirt1, key co-regulatory proteins, including serum- and glucocorticoid-induced kinase-1 and the putative transcription factor Af17, and targeted chromatin modifications. The complexes, through the action of Dot1a, maintain chromatin associated with the αENaC promoter in a stable hypermethylated state, constraining αENaC transcription under basal conditions. Aldosterone and serum- and glucocorticoid-induced kinase-1, itself, activate αENaC transcription in large part by disrupting or diminishing the Dot1a-Af9 and Dot1a-Sirt1 complexes and their effects on chromatin. Mouse models indicate potential roles of the Dot1a pathways in renal salt excretion and hypertension. [Copyright &y& Elsevier]

The article examines a direct correlation between Na(+) channel (ENaC) surface expression and the formation of cortical stiffness in endothelial cells in mice presenting with Liddle syndrome. It was revealed that stable knockdown of alphaENaC expression induced a heightened cortical stiffness. In conclusion, the disorder evokes enhanced ENaC expression and heightened cortical stiffness in vascular endothelial cells in situ.

Background/aims: Pseudohypoaldosteronism Type 1 (PHA1) is a rare heterogeneous syndrome characterized by severe salt loss, hyperkalemia, hyponatremia, metabolic acidosis, hyperaldosteronism and hyperreninemia. Multi-system form of PHA1 is caused by mutations in one of the genes encoding the α, β and γ subunits of epithelial sodium channels (ENaC). In this study, we presented a novel splice site mutation in the beta-gene of ENaC in a patient with multi-system PHA. Methods: We performed DNA sequencing analysis of SCNN1A, SCNN1B, SCNN1G and NR3C2 genes. Results: We found a novel c.1266-1G>C homozygous splice site mutation in intron 8 of the SCNN1B gene. Initially elevated plasma renin activity (PRA) and aldosterone levels of the patient returned to normal with large amounts of dietary salt and serum sodium (Na+) and potassium (K+) levels were within normal range at the end of the first year of life. Conclusion: This improvement may be due to partial activity of mutated ENaC subunits, reduced dependence on aldosterone in salt homeostasis with increasing age, and alternative regulating mechanisms in sodium homeostasis. The results enhance our understanding of the pathophysiology of this disorder and the mechanisms of renal salt conservation. [ABSTRACT FROM AUTHOR]

This article discusses a study which hypothesized that the phosphorylated form of the sodium chloride cotransporter or prostasin could serve as biomarkers for aldosteronism. Researchers tested the hypothesis in two animal models of aldosteronism and in patients with primary aldosteronism. They isolated urinary exosomes from 24-hour urine or spot urine using ultracentrifugation. The results showed that prostatin are promising markers for aldosteronism.

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The article presents a study which examines the relationship between common variants in the salt sensitivity and epithelial sodium channel (ENaC) genes of blood pressure (BP). The study conducted a community-based BP screening among 18-60 years old residing in villages to identify their family and potential probands. Results indicate that common variants of ENaC subunits may add to the variation of BP response to dietary sodium ingestion.

Copyright of Nefrologia is the property of Revista Nefrologia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The mechanotransduction mechanism underlying the myogenic response is poorly understood, but evidence implicates participation of epithelial sodium channel (ENaC)-like proteins. Therefore, the role of ENaC on the afferent arteriolar myogenic response was investigated in vitro using the blood-perfused juxtamedullary nephron technique. Papillectomy was used to isolate myogenic influences by eliminating tubuloglomerular feedback signals. Autoregulatory responses were assessed by manipulating perfusion pressure in 30-mm Hg steps. Under control conditions, arteriolar diameter increased by 15% from 13.0+/-1.3 to 14.7+/-1.2 microm (P<0.05) after reducing perfusion pressure from 100 to 70 mm Hg. Diameter decreased to 11.3+/-1.1 and 10.6+/-1.0 microm after increasing pressure to 130 and 160 mm Hg (88+/-1 and 81+/-2% of control diameter, P<0.05), respectively. Pressure-mediated autoregulatory responses were significantly inhibited by superfusion of 10 micromol/L amiloride (102+/-2, 97+/-4, and 94+/-3% of control diameter), or 10 micromol/L benzamil (106+/-5, 100+/-3, and 103+/-3% of control diameter), and when perfusing with blood containing 5 micromol/L amiloride (106+/-2, 97+/-4, and 97+/-4% of control diameter). Vasoconstrictor responses to 55 mmol/L KCl were preserved as diameters decreased by 67+/-4, 55+/-8, and 60+/-4% in afferent arterioles superfused with amiloride or benzamil, and perfused with amiloride, respectively. These responses were similar to responses obtained from control afferent arterioles (64+/-6%, P>0.05). Immunofluorescence revealed expression of the alpha, beta, and gamma subunits of ENaC in freshly isolated preglomerular microvascular smooth muscle cells. These results demonstrate that selective ENaC inhibitors attenuate afferent arteriolar myogenic responses and suggest that ENaC may function as mechanosensitive ion channels initiating pressure-dependent myogenic responses in rat juxtamedullary afferent arterioles. [ABSTRACT FROM AUTHOR]

Net sodium balances in humans are maintained through various ion transporters expressed along the entire nephron. Among these ion transporters, epithelial sodium channels (ENaC) located along the aldosterone-sensitive distal nephron (ASDN) play a pivotal role in the homeostasis of sodium balance. This is supported by analyses of inherited hypertensive disorders, showing that genes encoding ENaC and other modulatory proteins cause hereditary hypertension, such as Liddle syndrome. Among various modulating proteins, E3 ubiquitin ligase, Nedd4L, binds the PY motif of ENaC COOH terminals and catalyzes ubiquitination of the NH(2) terminus of the protein for subsequent degradation. Both evolutionarily conserved and evolutionarily new C2 domains of human Nedd4L, a cryptic splice variant resulting in a disrupted isoform product formed by a frame-shift mutation, were reported previously. We focused on one of the isoforms, isoform I, generated by SNP (rs4149601), and studied its expression and interactions with other isoforms by molecular biological, immunohistochemical, and electrophysiological methods. We found that isoform I may interact with other human isoforms in a dominant-negative fashion. Such interactions might abnormally increase sodium reabsorption. Taken together, our analyses suggest that the human Nedd4L gene, especially the evolutionarily new isoform I, is a candidate gene for hypertension. [ABSTRACT FROM AUTHOR]

One of the biggest challenges a newborn faces after birth is the task of making a smooth transition to air breathing. This task is complicated by the fact that fetal lungs are full of fluid which must be cleared rapidly to allow for gas exchange. Respiratory morbidity as a result of failure to clear fetal lung fluid is not uncommon, and can be particularly problematic in some infants delivered by elective cesarean delivery (ECS). Given the high rates of cesarean deliveries in the USA and worldwide, the public health and economic impact of morbidity in this subgroup is considerable. Whereas the occurrence of birth asphyxia, trauma, and meconium aspiration is reduced by elective Cesarean delivery, the risk of respiratory distress secondary to transient tachypnea of the newborn, surfactant deficiency, and pulmonary hypertension is increased. It is clear that physiologic events in the last few weeks of pregnancy coupled with the onset of spontaneous labor are accompanied by changes in the hormonal milieu of the fetus and its mother, resulting in preparation of the fetus for neonatal transition. Rapid clearance of fetal lung fluid is a key part of these changes, and is mediated in large part by transepithelial Na reabsorption through amiloride-sensitive Na channels in the alveolar epithelial cells, with only a limited contribution from mechanical factors and Starling forces. This chapter discusses the physiologic mechanisms underlying fetal lung fluid absorption and explores potential strategies for facilitating neonatal transition when infants are delivered by ECS before the onset of spontaneous labor. [Copyright &y& Elsevier]

Respiratory morbidity in near term (≥34 and <37 weeks) infants delivered spontaneously or by elective cesarean section (ECS) has been well documented in the literature, and accounts for a significant number of admissions to intensive care units among these neonates. Given the high rates of near-term deliveries in the USA and worldwide, the public health and economic impact of morbidity in this subgroup is considerable. Causes of respiratory distress include transient tachypnea of the newborn (TTNB), surfactant deficiency, pneumonia, and pulmonary hypertension. There is considerable evidence that physiologic events in the last few weeks of pregnancy coupled with the onset of spontaneous labor are accompanied by changes in the hormonal milieu of the fetus and its mother, resulting in rapid maturation and preparation of the fetus for delivery and neonatal transition. A surge in endogenous steroids and catecholamines accompanies term gestation and spontaneous vaginal delivery, and is responsible for some of the maturational effects. Rapid clearance of fetal lung fluid clearance plays a key role in the transition to air breathing. The bulk of this fluid clearance is mediated by transepithelial sodium reabsorption through amiloride-sensitive sodium channels in the alveolar epithelial cells with only a limited contribution from mechanical factors and Starling forces. Disruption of this process can lead to retention of fluid in air spaces, setting the stage for alveolar hypoventilation. When infants are delivered near-term, especially by cesarean section (repeat or primary) before the onset of spontaneous labor, the fetus is often deprived of these hormonal changes, making the neonatal transition more difficult. This chapter discusses the physiologic mechanisms underlying fetal lung fluid absorption and explores potential strategies for facilitating neonatal transition. [Copyright &y& Elsevier]

Sodium reabsorption in the distal nephron is tightly regulated in part by epithelial sodium channel (ENaC) and sodium chloride cotransporter (NCC), although non-invasive measure of these proteins in humans has not previously been feasible. We recently analyzed the urinary exosomal proteome and identified candidate targets for quantification of ENaC and NCC using targeted mass spectrometry.To test the hypothesis that urinary exosomal ENaC and NCC are altered during renin-angiotensin-aldosterone system activation, we activated the endogenous RAAS using a low sodium diet (LS) in two separate studies. We provided 8 subjects LS diet (10mmol/day for 7days) to assess urinary protein excretion at 7 days (study 1) and longitudinally over the course of 1 week (study 2). Daily 24-hour urine was collected to monitor sodium balance, and spot urine samples were obtained each morning on days 0, 2, 4, and 6 of LS diet. Urinary exosomal ENaC-α, ENaC-γ, and NCC peptides were analyzed using targeted multiple-reaction-monitoring analysis quantified with stable-isotope peptide standards, and results were normalized to urine creatinine concentration.In study 1, urinary ENaCγ increased after 8 days of LS diet (Figure A). In study 2, urinary exosomal ENaCγ (Figure B) and NCC peptides (Figure C) increased in a time-dependent manner during LS diet. These measures of urinary sodium channel expression may provide further insight into distal sodium reabsorption in human hypertension. [ABSTRACT FROM AUTHOR]