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We recently identified a pathway underlying immune activation in hypertension. Proteins oxidatively modified by reactive isoLG (isolevuglandin) accumulate in dendritic cells (DCs). PGE (Prostaglandin E2) has been implicated in the inflammation associated with hypertension. We hypothesized that PGE via its EP (E prostanoid) 3 receptor contributes to DC activation in hypertension. EP3 mice and wild-type littermates were exposed to sequential hypertensive stimuli involving an initial 2-week exposure to the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester hydrochloride in drinking water, followed by a 2-week washout period, and a subsequent 4% high-salt diet for 3 weeks. In wild-type mice, this protocol increased systolic pressure from 123±2 to 148±8 mm Hg (<0.05). This was associated with marked renal inflammation and a striking accumulation of isoLG adducts in splenic DCs. However, the increases in blood pressure, renal T-cell infiltration, and DC isoLG formation were completely prevented in EP3 mice. Similar protective effects were also observed in wild-type mice that received intracerebroventricular injection of a lentiviral vector encoding shRNA targeting the EP3 receptor. Further, in vitro experiments indicated that PGE also acts directly on DCs via its EP1 receptors to stimulate intracellular isoLG formation. Together, these findings provide new insight into how EP receptors in both the central nervous system and peripherally on DCs promote inflammation in salt-induced hypertension.
Dysregulation of sodium (Na) balance is a major cause of hypertensive cardiovascular disease. The current dogma is that interstitial Na readily equilibrates with plasma and that renal excretion and reabsorption is sufficient to regulate extracellular fluid volume and control blood pressure. These ideas have been recently challenged by the discovery that Na accumulates in tissues without commensurate volume retention and activates immune cells, leading to hypertension and autoimmune disease. However, objections have been raised to this new paradigm, with some investigators concerned about where and how salt is stored in tissues. Further concerns also include how Na is mobilized from tissue stores and how it interacts with various organ systems to cause hypertension and end-organ damage. This review assesses these two paradigms of Na regulation in the context of inflammation-mediated hypertension and cardiovascular disease pathogenesis. Also highlighted are future perspectives and important gaps in our understanding of how Na is linked to inflammation and hypertension. Understanding mechanisms of salt and body fluid regulation is the sine qua non of research efforts to identify therapeutic targets for hypertension and cardiovascular disease.
Copyright © 2017 the American Physiological Society.
This study describes a 13-yr-old girl with orthostatic intolerance, respiratory weakness, multiple endocrine abnormalities, pancreatic insufficiency, and multiorgan failure involving the gut and bladder. Exome sequencing revealed a de novo, loss-of-function allele in , the gene encoding the Na-K-2Cl cotransporter-1. The 11-bp deletion in exon 22 results in frameshift (p.Val1026Phe*2) and truncation of the carboxy-terminal tail of the cotransporter. Preliminary studies in heterologous expression systems demonstrate that the mutation leads to a nonfunctional transporter, which is expressed and trafficked to the plasma membrane alongside wild-type NKCC1. The truncated protein, visible at higher molecular sizes, indicates either enhanced dimerization or misfolded aggregate. No significant dominant-negative effect was observed. K transport experiments performed in fibroblasts from the patient showed reduced total and NKCC1-mediated K influx. The absence of a bumetanide effect on K influx in patient fibroblasts only under hypertonic conditions suggests a deficit in NKCC1 regulation. We propose that disruption in NKCC1 function might affect sensory afferents and/or smooth muscle cells, as their functions depend on NKCC1 creating a Cl gradient across the plasma membrane. This Cl gradient allows the γ-aminobutyric acid (GABA) receptor or other Cl channels to depolarize the membrane affecting processes such as neurotransmission or cell contraction. Under this hypothesis, disrupted sensory and smooth muscle function in a diverse set of tissues could explain the patient's phenotype.
Urinary exosomes secreted by multiple cell types in the kidney may participate in intercellular signaling and provide an enriched source of kidney-specific proteins for biomarker discovery. Factors that alter the exosomal protein content remain unknown. To determine whether endogenous and exogenous hormones modify urinary exosomal protein content, we analyzed samples from 14 mildly hypertensive patients in a crossover study during a high-sodium (HS, 160 mmol/d) diet and low-sodium (LS, 20 mmol/d) diet to activate the endogenous renin-angiotensin-aldosterone system. We further analyzed selected exosomal protein content in a separate cohort of healthy persons receiving intravenous aldosterone (0.7 μg/kg per hour for 10 hours) versus vehicle infusion. The LS diet increased plasma renin activity and aldosterone concentration, whereas aldosterone infusion increased only aldosterone concentration. Protein analysis of paired urine exosome samples by liquid chromatography-tandem mass spectrometry-based multidimensional protein identification technology detected 2775 unique proteins, of which 316 exhibited significantly altered abundance during LS diet. Sodium chloride cotransporter (NCC) and α- and γ-epithelial sodium channel (ENaC) subunits from the discovery set were verified using targeted multiple reaction monitoring mass spectrometry quantified with isotope-labeled peptide standards. Dietary sodium restriction or acute aldosterone infusion similarly increased urine exosomal γENaC[112-122] peptide concentrations nearly 20-fold, which correlated with plasma aldosterone concentration and urinary Na/K ratio. Urine exosomal NCC and αENaC concentrations were relatively unchanged during these interventions. We conclude that urinary exosome content is altered by renin-angiotensin-aldosterone system activation. Urinary measurement of exosomal γENaC[112-122] concentration may provide a useful biomarker of ENaC activation in future clinical studies.
Copyright © 2016 by the American Society of Nephrology.
CONTEXT - Interruption of the renin-angiotensin-aldosterone system prevents incident diabetes in high-risk individuals, although the mechanism remains unclear.
OBJECTIVE - To test the hypothesis that activation of the endogenous renin-angiotensin-aldosterone system or exogenous aldosterone impairs insulin secretion in humans.
DESIGN - We conducted a randomized, blinded crossover study of aldosterone vs vehicle and compared the effects of a low-sodium versus a high-sodium diet.
SETTING - Academic clinical research center.
PARTICIPANTS - Healthy, nondiabetic, normotensive volunteers.
INTERVENTIONS - Infusion of exogenous aldosterone (0.7 μg/kg/h for 12.5 h) or vehicle during low or high sodium intake. Low sodium (20 mmol/d; n = 12) vs high sodium (160 mmol/d; n = 17) intake for 5-7 days.
MAIN OUTCOME MEASURES - Change in acute insulin secretory response assessed during hyperglycemic clamps while in sodium balance during a low-sodium vs high-sodium diet during aldosterone vs vehicle.
RESULTS - A low-sodium diet increased endogenous aldosterone and plasma renin activity, and acute glucose-stimulated insulin (-16.0 ± 5.6%; P = .007) and C-peptide responses (-21.8 ± 8.4%; P = .014) were decreased, whereas the insulin sensitivity index was unchanged (-1.0 ± 10.7%; P = .98). Aldosterone infusion did not affect the acute insulin response (+1.8 ± 4.8%; P = .72) or insulin sensitivity index (+2.0 ± 8.8%; P = .78). Systolic blood pressure and serum potassium were similar during low and high sodium intake and during aldosterone infusion.
CONCLUSIONS - Low dietary sodium intake reduces insulin secretion in humans, independent of insulin sensitivity.
Gastric adenocarcinoma is a leading cause of cancer-related death worldwide, and Helicobacter pylori infection is one of the strongest known risk factors for this malignancy. H. pylori strains exhibit a high level of genetic diversity, and the risk of gastric cancer is higher in persons carrying certain strain types (for example, those that contain a cag pathogenicity island or type s1 vacA alleles) than in persons carrying other strain types. Additional risk factors for gastric cancer include specific human genetic polymorphisms and specific dietary preferences (for example, a high-salt diet or a diet deficient in fruits and vegetables). Finally, iron-deficiency anemia is a risk factor for gastric cancer. Recent studies have provided evidence that several dietary risk factors for gastric cancer directly impact H. pylori virulence. In this review article, we discuss mechanisms by which diet can modulate H. pylori virulence and thereby influence gastric cancer risk.
The steroid hormone aldosterone regulates sodium and potassium homeostasis. Aldosterone and activation of the mineralocorticoid receptor also causes inflammation and fibrosis of the heart, fibrosis and remodelling of blood vessels and tubulointerstitial fibrosis and glomerular injury in the kidney. Aldosterone and mineralocorticoid-receptor activation initiate an inflammatory response by increasing the generation of reactive oxygen species by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondria. High salt intake potentiates these effects, in part by activating the Rho family member Rac1, a regulatory subunit of reduced NADPH oxidase that activates the mineralocorticoid receptor. Studies in mice in which the mineralocorticoid receptor has been deleted from specific cell types suggest a key role for macrophages in promoting inflammation and fibrosis. Aldosterone can exert mineralocorticoid-receptor-independent effects via the angiotensin II receptor and via G-protein-coupled receptor 30. Mineralocorticoid-receptor antagonists are associated with decreased mortality in patients with heart disease and show promise in patients with kidney injury, but can elevate serum potassium concentration. Studies in rodents genetically deficient in aldosterone synthase or treated with a pharmacological aldosterone-synthase inhibitor are providing insight into the relative contribution of aldosterone compared with the contribution of mineralocorticoid-receptor activation in inflammation, fibrosis, and injury. Aldosterone-synthase inhibitors are under development in humans.
AIMS - Chronic excess salt intake may have blood pressure-independent adverse effects on the heart such as myocardial hypertrophy and fibrosis. Effects of subacute sodium loading with excess dietary salt on diastolic function in normotensive individuals have been conflicting and the mechanisms are poorly understood.
METHODS AND RESULTS - Thirteen healthy normotensive subjects (age 24 ± 4 years) entered a 2-week crossover study with 1 week of a low-salt diet <10 mEq/day and 1 week of a high-salt diet >200 mEq/day. At the end of each study week, left ventricular dimensions, systolic, and diastolic function were assessed with echocardiography before and after 2 L of normal saline infusion. One week of high-salt and low-salt diets did not lead to differences in echocardiographic parameters of systolic or diastolic function, even after rapid volume expansion with saline infusion. The peak early diastolic strain rate (SR) increased after volume loading both after completion of low-salt (1.62 ± 0.23/s vs. 1.82 ± 0.14/s, P < 0.05) and high-salt diets (1.67 ± 0.16/s vs. 1.86 ± 0.22/s, P < 0.05). There was a positive correlation between the peak early diastolic SR and the cardiac index (r = 0.52, P = 0.017).
CONCLUSION - In healthy normotensive individuals, subacute excess dietary sodium intake does not affect diastolic function. The peak early diastolic SR, similar to other mitral Doppler and tissue Doppler parameters of diastolic function, appears to be strongly dependent on pre-load.
Mutations in α, β, or γ subunits of the epithelial sodium channel (ENaC) can downregulate ENaC activity and cause a severe salt-losing syndrome with hyperkalemia and metabolic acidosis, designated pseudohypoaldosteronism type 1 in humans. In contrast, mice with selective inactivation of αENaC in the collecting duct (CD) maintain sodium and potassium balance, suggesting that the late distal convoluted tubule (DCT2) and/or the connecting tubule (CNT) participates in sodium homeostasis. To investigate the relative importance of ENaC-mediated sodium absorption in the CNT, we used Cre-lox technology to generate mice lacking αENaC in the aquaporin 2-expressing CNT and CD. Western blot analysis of microdissected cortical CD (CCD) and CNT revealed absence of αENaC in the CCD and weak αENaC expression in the CNT. These mice exhibited a significantly higher urinary sodium excretion, a lower urine osmolality, and an increased urine volume compared with control mice. Furthermore, serum sodium was lower and potassium levels were higher in the genetically modified mice. With dietary sodium restriction, these mice experienced significant weight loss, increased urinary sodium excretion, and hyperkalemia. Plasma aldosterone levels were significantly elevated under both standard and sodium-restricted diets. In summary, αENaC expression within the CNT/CD is crucial for sodium and potassium homeostasis and causes signs and symptoms of pseudohypoaldosteronism type 1 if missing.