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1.
Nature ; 551(7682): 585-589, 2017 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-29143823

RESUMO

A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (TH17) cells, which can also contribute to hypertension. Induction of TH17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus. Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating TH17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased TH17 cells and increased blood pressure. Our results connect high salt intake to the gut-immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Lactobacillus/efeitos dos fármacos , Lactobacillus/isolamento & purificação , Cloreto de Sódio/farmacologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Animais , Autoimunidade/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/microbiologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/terapia , Fezes/microbiologia , Humanos , Hipertensão/induzido quimicamente , Ácidos Indolacéticos/metabolismo , Indóis/metabolismo , Intestinos/citologia , Intestinos/efeitos dos fármacos , Intestinos/imunologia , Intestinos/microbiologia , Lactobacillus/imunologia , Ativação Linfocitária/efeitos dos fármacos , Contagem de Linfócitos , Masculino , Camundongos , Projetos Piloto , Cloreto de Sódio/administração & dosagem , Simbiose , Células Th17/citologia , Triptofano/metabolismo
2.
Pflugers Arch ; 473(6): 897-910, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34028587

RESUMO

We discovered high Na+ and water content in the skin of newborn Sprague-Dawley rats, which reduced ~ 2.5-fold by 7 days of age, indicating rapid changes in extracellular volume (ECV). Equivalent changes in ECV post birth were also observed in C57Bl/6 J mice, with a fourfold reduction over 7 days, to approximately adult levels. This established the generality of increased ECV at birth. We investigated early sodium and water handling in neonates from a second rat strain, Fischer, and an Hsd11b2-knockout rat modelling the syndrome of apparent mineralocorticoid excess (SAME). Despite Hsd11b2-/- animals exhibiting lower skin Na+ and water levels than controls at birth, they retained ~ 30% higher Na+ content in their pelts at the expense of K+ thereafter. Hsd11b2-/- neonates exhibited incipient hypokalaemia from 15 days of age and became increasingly polydipsic and polyuric from weaning. As with adults, they excreted a high proportion of ingested Na+ through the kidney, (56.15 ± 8.21% versus control 34.15 ± 8.23%; n = 4; P < 0.0001), suggesting that changes in nephron electrolyte transporters identified in adults, by RNA-seq analysis, occur by 4 weeks of age. Our data reveal that Na+ imbalance in the Hsd11b2-/- neonate leads to excess Na+ storage in skin and incipient hypokalaemia, which, together with increased, glucocorticoid-induced Na+ uptake in the kidney, then contribute to progressive, volume contracted, salt-sensitive hypertension. Skin Na+ plays an important role in the development of SAME but, equally, may play a key physiological role at birth, supporting post-natal growth, as an innate barrier to infection or as a rudimentary kidney.


Assuntos
Pressão Sanguínea , Síndrome de Excesso Aparente de Minerolocorticoides/metabolismo , Pele/metabolismo , Sódio/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Animais , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Síndrome de Excesso Aparente de Minerolocorticoides/fisiopatologia , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley
3.
Am J Physiol Renal Physiol ; 319(1): F1-F7, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32463729

RESUMO

Albuminuria in the pathological range is a significant predictor of preeclampsia. In healthy persons, high normal urinary albumin predicts a later incidence of hypertension and is associated with salt sensitivity of blood pressure. We hypothesized that in pregnancy urinary albumin in the normal range associates with blood pressure through activation of distal Na+ reabsorption and renal salt retention by plasma factors cofiltered with albumin. We analyzed 24-h urine collections and plasma samples from gestational week 29 of 560 pregnant women from the Odense Child Cohort, a Danish population-based cohort. Plasma and urinary aldosterone were measured by ELISA. Plasma and urinary Na+, K+, Cl-, and creatinine were also determined. Predictive values of urinary albumin were assessed by linear mixed, multiple, and Cox regression analyses. Primary outcomes were blood pressure and renal electrolyte handling. Twenty-four-hour urinary albumin excretion at gestational week 29 associated with gestational blood pressure trajectory, with adjusted ß coefficients (95% confidence intervals) for each 10-fold increase in urinary albumin as follows: 5.71 (1.60 to 9.81) mmHg for systolic blood pressure and 4.39 (1.41 to 7.38) mmHg for diastolic blood pressure. Urinary albumin was inversely associated with fractional excretion rates of Na+, K+, and Cl-, with adjusted ß coefficients (95% confidence intervals) for each 10-fold increase in urine albumin as follows: -0.25 (-0.35 to -0.14), -5.06 (-6.81 to -3.30), and -0.28 (-0.41 to -0.15), respectively. In conclusion, at gestational week 29, urinary albumin excretion in the normal range associated with blood pressure and renal electrolyte handling independent of potential confounders.


Assuntos
Albuminúria/fisiopatologia , Pressão Sanguínea/fisiologia , Rim/fisiologia , Adulto , Feminino , Humanos , Gravidez , Valores de Referência , Adulto Jovem
4.
Int J Obes (Lond) ; 44(5): 1119-1128, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31819201

RESUMO

BACKGROUND: Physical activity improves insulin sensitivity in obesity. Hypoxia training is claimed to augment this effect. We tested the hypothesis that normobaric hypoxia training would improve insulin sensitivity in obese patients with metabolic syndrome. METHODS: In a randomized controlled trial, 23 obese men with metabolic syndrome who were not informed of the FiO2 conditions underwent a 6-week physical exercise intervention under ambient (n = 11; FiO2 21%) conditions or hypoxia (n = 12; FiO2 15%) using a normobaric hypoxic chamber. Three 60-min sessions of interval training were performed each week at 60% of individual V̇O2max. Assessment of myocellular insulin sensitivity by euglycemic hyperinsulinemic clamp was performed in 21 of these subjects before and after 6 weeks of training. Comprehensive phenotyping also included biopsies of subcutaneous adipose tissues. RESULTS: The intermittent moderate physical exercise protocol did not substantially change the myocellular insulin sensitivity within 6 weeks under normoxic conditions (ISIClamp: 0.035 (IQR 0.016-0.075) vs. 0.037 (IQR 0.026-0.056) mg* kg-1 *min-1/(mU* l-1); p = 0.767). In contrast, ISIClamp improved during hypoxia training (0.028 (IQR 0.018-0.035) vs. 0.038 (IQR 0.024-0.060) mg * kg-1 *min-1/(mU *l-1); p < 0.05). Between group comparison of ISIClamp change revealed a small difference between groups (Cohen's d = 0.26). Within the hypoxic group, improvement of ISIClamp during training was associated with individual increase of circulating vascular endothelial growth factor (VEGF) levels (r = 0.678, p = 0.015), even if mean VEGF levels were not modified by any training condition. Atrial natriuretic peptide (ANP) system components were not associated with increased ISIClamp during hypoxic training. CONCLUSIONS: Physical training under hypoxic conditions could partially augment the favorable effects of exercise alone on myocellular insulin sensitivity in obese men with metabolic syndrome. Concomitant changes in VEGF might represent an underlying pathophysiological mechanism.


Assuntos
Exercício Físico/fisiologia , Resistência à Insulina/fisiologia , Síndrome Metabólica , Músculo Esquelético/metabolismo , Obesidade , Idoso , Humanos , Hipóxia , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/metabolismo , Síndrome Metabólica/terapia , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Obesidade/terapia , Oxigênio/metabolismo , Fator A de Crescimento do Endotélio Vascular/sangue
5.
Arterioscler Thromb Vasc Biol ; 38(9): 2054-2064, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30354256

RESUMO

Objective- A commonly accepted pivotal mechanism in fluid volume and blood pressure regulation is the parallel relationship between body Na+ and extracellular fluid content. Several recent studies have, however, shown that a considerable amount of Na+ can be retained in skin without commensurate water retention. Here, we asked whether a salt accumulation shown to result in VEGF (vascular endothelial growth factor)-C secretion and lymphangiogenesis had any influence on lymphatic function. Approach and Results- By optical imaging of macromolecular tracer washout in skin, we found that salt accumulation resulted in an increase in lymph flow of 26% that was noticeable only after including an overnight recording period. Surprisingly, lymph flow in skeletal muscle recorded with a new positron emission tomography/computed tomography method was also increased after salt exposure. The transcapillary filtration was unaffected by the high-salt diet and deoxycorticosterone-salt treatment, suggesting that the capillary barrier was not influenced by the salt accumulation. A significant reduction in lymph flow after depletion of macrophages/monocytes by clodronate suggests these cells are involved in the observed lymph flow response, together with collecting vessels shown here to enhance their contraction frequency as a response to extracellular Na+. Conclusions- The observed changes in lymph flow suggest that the lymphatics may influence long-term regulation of tissue fluid balance during salt accumulation by contributing to fluid homeostasis in skin and muscle. Our studies identify lymph clearance as a potential disease-modifying factor that might be targeted in conditions characterized by salt accumulation like chronic kidney disease and salt-sensitive hypertension.


Assuntos
Linfa/metabolismo , Linfangiogênese/efeitos dos fármacos , Músculo Esquelético/metabolismo , Pele/metabolismo , Cloreto de Sódio na Dieta/efeitos adversos , Animais , Ácido Clodrônico/farmacologia , Linfa/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Sistema Fagocitário Mononuclear/efeitos dos fármacos , Sistema Fagocitário Mononuclear/metabolismo , Músculo Esquelético/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Ratos Sprague-Dawley , Pele/diagnóstico por imagem , Fator C de Crescimento do Endotélio Vascular/metabolismo , Equilíbrio Hidroeletrolítico
6.
Nephrol Dial Transplant ; 31(7): 1078-81, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26410883

RESUMO

Sodium balance is achieved within a matter of days and everything that enters should come out; sodium stores are of questionable relevance and sodium accumulation is accompanied by weight gain. Careful balance studies oftentimes conflicted with this view, and long-term studies suggested that total body sodium (TBNa) fluctuates independent of intake or body weight. We recently performed the opposite experiment in that we fixed sodium intake for weeks at three levels of sodium intake and collected all urine made. We found weekly (circaseptan) patterns in sodium excretion that were inversely related to aldosterone and directly related to cortisol. TBNa was not dependent on sodium intake, but instead exhibited far longer (greater than or equal to monthly) infradian rhythms independent of extracellular water, body weight or blood pressure. To discern the mechanisms further, we delved into sodium magnetic resonance imaging (Na-MRI) to identify sodium storage clinically. We found that sodium stores are greater in men than in women, increase with age and are higher in hypertensive than normotensive persons. We have suggestive evidence that these sodium stores can be mobilized, also in dialysis patients. The observations are in accordance with our findings that immune cells regulate a hypertonic interface in the skin interstitium that could serve as a protective barrier. Returning to our balance studies, we found that due to biological variability in 24-h sodium excretion, collecting urine for a day could not separate 12, 9 or 6 g/day sodium intakes with the precision of tossing a coin. Every other daily urine sampling correctly classified a 3-g difference in salt intake less than half the time, making the gold standard 24-h urine collection of little value in predicting salt intake. We suggest that wobbles in expected outcomes can lead to novel clinical insights even with respect to banal salt questions.


Assuntos
Cloreto de Sódio/metabolismo , Equilíbrio Hidroeletrolítico , Animais , Humanos , Cloreto de Sódio/administração & dosagem
7.
NMR Biomed ; 28(1): 54-62, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25328128

RESUMO

Skin sodium (Na(+) ) storage, as a physiologically important regulatory mechanism for blood pressure, volume regulation and, indeed, survival, has recently been rediscovered. This has prompted the development of MRI methods to assess Na(+) storage in humans ((23) Na MRI) at 3.0 T. This work examines the feasibility of high in-plane spatial resolution (23) Na MRI in skin at 7.0 T. A two-channel transceiver radiofrequency (RF) coil array tailored for skin MRI at 7.0 T (f = 78.5 MHz) is proposed. Specific absorption rate (SAR) simulations and a thorough assessment of RF power deposition were performed to meet the safety requirements. Human skin was examined in an in vivo feasibility study using two-dimensional gradient echo imaging. Normal male adult volunteers (n = 17; mean ± standard deviation, 46 ± 18 years; range, 20-79 years) were investigated. Transverse slices of the calf were imaged with (23) Na MRI using a high in-plane resolution of 0.9 × 0.9 mm(2) . Skin Na(+) content was determined using external agarose standards covering a physiological range of Na(+) concentrations. To assess the intra-subject reproducibility, each volunteer was examined three to five times with each session including a 5-min walk and repositioning/preparation of the subject. The age dependence of skin Na(+) content was investigated. The (23) Na RF coil provides improved sensitivity within a range of 1 cm from its surface versus a volume RF coil which facilitates high in-plane spatial resolution imaging of human skin. Intra-subject variability of human skin Na(+) content in the volunteer population was <10.3%. An age-dependent increase in skin Na(+) content was observed (r = 0.78). The assignment of Na(+) stores with (23) Na MRI techniques could be improved at 7.0 T compared with current 3.0 T technology. The benefits of such improvements may have the potential to aid basic research and clinical applications designed to unlock questions regarding the Na(+) balance and Na(+) storage function of skin.


Assuntos
Imageamento por Ressonância Magnética/métodos , Pele/metabolismo , Sódio/metabolismo , Adulto , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Imagens de Fantasmas , Prótons , Ondas de Rádio , Reprodutibilidade dos Testes , Razão Sinal-Ruído , Adulto Jovem
8.
Kidney Int ; 85(4): 759-67, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24107854

RESUMO

Current teaching states that when sodium intake is increased from low to high levels, total-body sodium (TBNa) and water increase until daily sodium excretion again equals intake. When sodium intake is reduced, sodium excretion briefly exceeds intake until the excess TBNa and water are eliminated, at which point sodium excretion again equals intake. However, careful balance studies oftentimes conflict with this view and long-term studies suggest that TBNa fluctuates independent of intake or body weight. We recently performed the opposite experiment in that we fixed sodium intake for several weeks at three levels of sodium intake and collected all urine made. We found weekly (circaseptan) patterns in sodium excretion that were inversely related to aldosterone and directly to cortisol. TBNa was not dependent on sodium intake but instead exhibited far longer (≥ monthly) infradian rhythms independent of extracellular water, body weight, or blood pressure. The findings are consistent with our ideas on tissue sodium storage and its regulation that we developed on the basis of animal research. We are implementing (23)Na-magnetic resonance imaging (MRI) to pursue open questions on sodium balance in patients. Our findings could be relevant to therapeutic strategies for hypertension and target-organ damage.


Assuntos
Sódio/urina , Equilíbrio Hidroeletrolítico , Animais , Humanos , Sódio/administração & dosagem
9.
J Invest Dermatol ; 142(1): 166-178.e8, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34237339

RESUMO

Sodium can accumulate in the skin at concentrations exceeding serum levels. A high sodium environment can lead to pathogenic T helper 17 cell expansion. Psoriasis is a chronic inflammatory skin disease in which IL-17‒producing T helper 17 cells play a crucial role. In an observational study, we measured skin sodium content in patients with psoriasis and in age-matched healthy controls by Sodium-23 magnetic resonance imaging. Patients with PASI > 5 showed significantly higher sodium and water content in the skin but not in other tissues than those with lower PASI or healthy controls. Skin sodium concentrations measured by Sodium-23 spectroscopy or by atomic absorption spectrometry in ashed-skin biopsies verified the findings with Sodium-23 magnetic resonance imaging. In vitro T helper 17 cell differentiation of naive CD4+ cells from patients with psoriasis markedly induced IL-17A expression under increased sodium chloride concentrations. The imiquimod-induced psoriasis mouse model replicated the human findings. Extracellular tracer Chromium-51-EDTA measurements in imiquimod- and sham-treated skin showed similar extracellular volumes, rendering excessive water of intracellular origin. Chronic genetic IL-17A‒driven psoriasis mouse models underlined the role of IL-17A in dermal sodium accumulation and inflammation. Our data describe skin sodium as a pathophysiological feature of psoriasis, which could open new avenues for its treatment.


Assuntos
Interleucina-17/metabolismo , Psoríase/metabolismo , Pele/metabolismo , Sódio/análise , Células Th17/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Humanos , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Índice de Gravidade de Doença , Pele/patologia , Cloreto de Sódio/metabolismo , Espectrofotometria Atômica , Análise Espectral
10.
Acta Physiol (Oxf) ; 232(1): e13628, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33590724

RESUMO

AIM: Recent evidence suggests that arterial hypertension could be alternatively explained as a physiological adaptation response to water shortage, termed aestivation, which relies on complex multi-organ metabolic adjustments to prevent dehydration. Here, we tested the hypothesis that chronic water loss across diseased skin leads to similar adaptive water conservation responses as observed in experimental renal failure or high salt diet. METHODS: We studied mice with keratinocyte-specific overexpression of IL-17A which develop severe psoriasis-like skin disease. We measured transepidermal water loss and solute and water excretion in the urine. We quantified glomerular filtration rate (GFR) by intravital microscopy, and energy and nitrogen pathways by metabolomics. We measured skin blood flow and transepidermal water loss (TEWL) in conjunction with renal resistive indices and arterial blood pressure. RESULTS: Psoriatic animals lost large amounts of water across their defective cutaneous epithelial barrier. Metabolic adaptive water conservation included mobilization of nitrogen and energy from muscle to increase organic osmolyte production, solute-driven maximal anti-diuresis at normal GFR, increased metanephrine and angiotensin 2 levels, and cutaneous vasoconstriction to limit TEWL. Heat exposure led to cutaneous vasodilation and blood pressure normalization without parallel changes in renal resistive index, albeit at the expense of further increased TEWL. CONCLUSION: Severe cutaneous water loss predisposes psoriatic mice to lethal dehydration. In response to this dehydration stress, the mice activate aestivation-like water conservation motifs to maintain their body hydration status. The circulatory water conservation response explains their arterial hypertension. The nitrogen-dependency of the metabolic water conservation response explains their catabolic muscle wasting.


Assuntos
Hipertensão , Perda Insensível de Água , Animais , Estivação , Camundongos , Músculos , Pele
11.
Per Med ; 16(5): 369-378, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31552798

RESUMO

Aim: The purpose of our study was to analyze the predictive ability of the multiplicative model of genetic risk of nonlacunar ischemic stroke (IS) for independent samples from Russia. Patients & methods: A total of 181 patients and 360 healthy controls were included in this study. The discriminative accuracy of model was evaluated by the area under the receiver operating characteristic curve (AUC). Results: Classification model based on 15 single-nucleotide polymorphisms (SNPs), which are associated with a cardioembolic subtype of IS, had an AUC of 0.62 in patients with corresponding subtypes and an AUC of 0.58 for all patients. Conclusion: Risk calculation approach based on IS-associated SNPs had satisfactory performance in predicting the predisposition to the disease.


Assuntos
Isquemia Encefálica/genética , Testes Genéticos/métodos , Acidente Vascular Cerebral/genética , Adulto , Idoso , Área Sob a Curva , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Medicina de Precisão/métodos , Curva ROC , Fatores de Risco , Federação Russa
12.
Hypertension ; 74(2): 391-398, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31177907

RESUMO

The mineralocorticoid aldosterone increases in plasma in healthy pregnancy along with renin and angiotensin II and plays a key role in the physiological plasma volume expansion. In mice, aldosterone contributes to an optimal fetal development by enhancing PlGF (placental growth factor) expression and trophoblast cell proliferation. In preeclampsia, there is coincident suppression of aldosterone and impaired placental development. We hypothesized that aldosterone independently contributes to placental and birth weight in humans, and high dietary sodium and low potassium intakes affect this relationship adversely. We analyzed 24-hour urine collections and plasma samples from gestational week 29 in a subsample of 569 pregnant women from the Odense Child Cohort-a Danish population-based longitudinal cohort study. Plasma and urinary aldosterone were measured by ELISA, sodium and potassium excretions by flame photometer. Predictive values of aldosterone levels and sodium and potassium intakes were assessed by multiple and Cox regression analyses. Primary outcomes were placental weight and birth weight. Secondary outcome was preeclampsia. Urinary aldosterone excretion at gestational week 29 independently contributed to placental and birth weights (adjusted ß-coefficients [95% CI], 24.50 [9.66-39.35] and 9.59 [4.57-14.61], respectively). Aldosterone levels were not associated to preeclampsia incidence. Salt intake >6 g/d was associated with development of preeclampsia (hazard ratio [95% CI], 5.68 [1.51-21.36]). At gestational week 29, urinary aldosterone excretion is an independent predictor of placental and birth weights. High salt intake is a risk factor for preeclampsia. In perspective, suppression of aldosterone in pregnancy has adverse trophic effects.


Assuntos
Aldosterona/sangue , Potássio/metabolismo , Pré-Eclâmpsia/etiologia , Resultado da Gravidez , Cloreto de Sódio na Dieta/efeitos adversos , Adulto , Estudos de Coortes , Dinamarca , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Incidência , Modelos Lineares , Estudos Longitudinais , Pré-Eclâmpsia/metabolismo , Valor Preditivo dos Testes , Gravidez , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Cloreto de Sódio na Dieta/metabolismo , Estatísticas não Paramétricas
13.
FEBS Lett ; 582(6): 874-80, 2008 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-18291104

RESUMO

We tested the hypothesis that nitric oxide (NO) plays an important role in cytokinin signaling. Inhibitors of NO-synthase (NOS), L-NMMA and L-NAME, inhibited the expression of the GUS gene controlled by the cytokinin-responsive ARR5 promoter. However, the inactive analogues D-NMMA and D-NAME had a similar inhibitory activity. NO donors alone did not induce GUS activity and the NO scavenger cPTIO did not prevent the induction of the ARR5 promoter by cytokinin. Northern blot analysis of the P(ARR5)::GUS transgene and the host ARR5 gene revealed that cytokinin-induced transcript accumulation was not altered by NMMA-treatment, indicating that NMMA acts post-transcriptionally. Together the data show that NO has no direct role in eliciting the primary cytokinin response in plants.


Assuntos
Arabidopsis/metabolismo , Citocininas/metabolismo , Óxido Nítrico/metabolismo , Arabidopsis/efeitos dos fármacos , Arabidopsis/genética , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica de Plantas , Genes Reporter/efeitos dos fármacos , Glucuronidase/genética , NG-Nitroarginina Metil Éster/farmacologia , Doadores de Óxido Nítrico/farmacologia , Plantas Geneticamente Modificadas , Regiões Promotoras Genéticas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , ômega-N-Metilarginina/farmacologia
14.
Physiol Rep ; 6(24): e13949, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30565412

RESUMO

The evidence that physical exercise lowers metabolic and cardiovascular risk is undisputed. Normobaric hypoxia training has been introduced to facilitate the effects of exercise. We tested the hypothesis that hypoxia training augments exercise-related effects. We randomized 23 men with metabolic-syndrome to single-blinded exercise at normoxia (FiO2 21%) or hypoxia (FiO2 15%). Six weeks endurance training on a treadmill, 3 days per week, over 60 min at 60% VO2 max was required. The study included the following: (1) metabolic phenotyping by indirect calorimetry and adipose and muscle tissue microdialysis to gain insight into effects on resting, postprandial, and exercise metabolism, (2) cardiac imaging, and (3) biopsies. Primary endpoint was the change in cardiorespiratory fitness; secondary endpoints were as follows: changes in body weight, waist circumference, blood pressure, cardiac dimensions, and adipose and muscle tissue metabolism and gene expression. Our subjects reduced waist circumference and improved several cardiovascular risk markers including blood pressure. However, these effects were similar in both training groups. Cardiac dimensions were not influenced. We focused on glucose metabolism. After an oral glucose load, adipose tissue metabolism was significantly shifted to a more lipolytic state under hypoxia, whereas muscle metabolism was similar under both conditions. Postprandial energy expenditure was significantly increased under hypoxia, whereas activity energy expenditure was improved under normoxia. Gene expression was not consistently influenced by FiO2 . Adipose tissue triglyceride lipase, leptin, and hypoxia-inducible factor-alpha expression were increased by normoxia but not hypoxia.


Assuntos
Treino Aeróbico/métodos , Hipóxia/fisiopatologia , Síndrome Metabólica/terapia , Consumo de Oxigênio , Tecido Adiposo/fisiologia , Glicemia/metabolismo , Pressão Sanguínea , Peso Corporal , Aptidão Cardiorrespiratória , Humanos , Masculino , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Músculo Esquelético/fisiologia
15.
Hypertension ; 69(4): 660-668, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28167686

RESUMO

The common notion is that the body Na+ is maintained within narrow limits for fluid and blood pressure homeostasis. Several studies have, however, shown that considerable amounts of Na+ can be retained or removed from the body without commensurate water loss and that the skin can serve as a major salt reservoir. Our own data from rats have suggested that the skin is hypertonic compared with plasma on salt storage and that this also applies to skin interstitial fluid. Even small electrolyte gradients between plasma and interstitial fluid would represent strong edema-generating forces. Because the water accumulation has been shown to be modest, we decided to reexamine with alternative methods in rats whether interstitial fluid is hypertonic during salt accumulation induced by high-salt diet (8% NaCl and 1% saline to drink) or deoxycorticosterone pellet implantation. These treatments resulted both in increased systemic blood pressure, skin salt, and water accumulation and in skin hyperosmolality. Interstitial fluid isolated from implanted wicks and lymph draining the skin was, however, isosmotic, and Na+ concentration in fluid isolated by centrifugation and in lymph was not different from plasma. Interestingly, by eluting layers of the skin, we could show that there was an osmolality and urea gradient from epidermis to dermis. Collectively, our data suggest that fluid leaving the skin as lymph is isosmotic to plasma but also that the skin can differentially control its own electrolyte microenvironment by creating local gradients that may be functionally important.


Assuntos
Pressão Sanguínea/fisiologia , Líquido Extracelular/metabolismo , Hipertensão/metabolismo , Linfa/metabolismo , Pele/metabolismo , Cloreto de Sódio na Dieta/efeitos adversos , Desequilíbrio Hidroeletrolítico/metabolismo , Animais , Modelos Animais de Doenças , Hipertensão/etiologia , Hipertensão/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Equilíbrio Hidroeletrolítico , Desequilíbrio Hidroeletrolítico/complicações
16.
Hypertension ; 69(5): 919-926, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28320855

RESUMO

In response to salt loading, Na+ and Cl- accumulate in the skin in excess of water, stimulating skin lymphangiogenesis via activation of the mononuclear phagocyte system cell-derived vascular endothelial growth factor-C-vascular endothelial growth factor type 3 receptor signaling pathway. Inhibition of this pathway results in salt-sensitive hypertension. Sunitinib is an antiangiogenic, anticancer agent that blocks all 3 vascular endothelial growth factor receptors and increases blood pressure. We explored the salt dependency of sunitinib-induced hypertension and whether impairment of skin lymphangiogenesis is an underlying mechanism. Normotensive Wistar-Kyoto rats were exposed to a normal or high salt with or without sunitinib administration. Sunitinib induced a 15 mm Hg rise in telemetrically measured blood pressure, which was aggravated by a high-salt diet (HSD), resulting in a decline of the slope of the pressure-natriuresis curve. Without affecting body weight, plasma Na+ concentration or renal function, Na+ and Cl- skin content increased by 31% and 32% with the high salt and by 49% and 50% with the HSD plus sunitinib, whereas skin water increased by 17% and 24%, respectively. Skin mononuclear phagocyte system cell density increased both during sunitinib and a HSD, but no further increment was seen when HSD and sunitinib were combined. HSD increased skin lymphangiogenesis, while sunitinib tended to decrease lymphangiogenesis, both during a normal-salt diet and HSD. We conclude that sunitinib induces hypertension that is aggravated by high salt intake and not accompanied by impaired skin lymphangiogenesis.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Hipertensão/fisiopatologia , Pele/efeitos dos fármacos , Sódio na Dieta/administração & dosagem , Animais , Hipertensão/induzido quimicamente , Indóis , Linfangiogênese/efeitos dos fármacos , Masculino , Pirróis , Ratos , Ratos Endogâmicos WKY , Pele/fisiopatologia , Sunitinibe
17.
J Clin Invest ; 127(5): 1932-1943, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28414302

RESUMO

BACKGROUND: The idea that increasing salt intake increases drinking and urine volume is widely accepted. We tested the hypothesis that an increase in salt intake of 6 g/d would change fluid balance in men living under ultra-long-term controlled conditions. METHODS: Over the course of 2 separate space flight simulation studies of 105 and 205 days' duration, we exposed 10 healthy men to 3 salt intake levels (12, 9, or 6 g/d). All other nutrients were maintained constant. We studied the effect of salt-driven changes in mineralocorticoid and glucocorticoid urinary excretion on day-to-day osmolyte and water balance. RESULTS: A 6-g/d increase in salt intake increased urine osmolyte excretion, but reduced free-water clearance, indicating endogenous free water accrual by urine concentration. The resulting endogenous water surplus reduced fluid intake at the 12-g/d salt intake level. Across all 3 levels of salt intake, half-weekly and weekly rhythmical mineralocorticoid release promoted free water reabsorption via the renal concentration mechanism. Mineralocorticoid-coupled increases in free water reabsorption were counterbalanced by rhythmical glucocorticoid release, with excretion of endogenous osmolyte and water surplus by relative urine dilution. A 6-g/d increase in salt intake decreased the level of rhythmical mineralocorticoid release and elevated rhythmical glucocorticoid release. The projected effect of salt-driven hormone rhythm modulation corresponded well with the measured decrease in water intake and an increase in urine volume with surplus osmolyte excretion. CONCLUSION: Humans regulate osmolyte and water balance by rhythmical mineralocorticoid and glucocorticoid release, endogenous accrual of surplus body water, and precise surplus excretion. FUNDING: Federal Ministry for Economics and Technology/DLR; the Interdisciplinary Centre for Clinical Research; the NIH; the American Heart Association (AHA); the Renal Research Institute; and the TOYOBO Biotechnology Foundation. Food products were donated by APETITO, Coppenrath und Wiese, ENERVIT, HIPP, Katadyn, Kellogg, Molda, and Unilever.


Assuntos
Glucocorticoides/metabolismo , Mineralocorticoides/metabolismo , Cloreto de Sódio na Dieta/administração & dosagem , Voo Espacial , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Água/metabolismo , Adulto , Humanos , Masculino
18.
J Clin Invest ; 127(5): 1944-1959, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28414295

RESUMO

Natriuretic regulation of extracellular fluid volume homeostasis includes suppression of the renin-angiotensin-aldosterone system, pressure natriuresis, and reduced renal nerve activity, actions that concomitantly increase urinary Na+ excretion and lead to increased urine volume. The resulting natriuresis-driven diuretic water loss is assumed to control the extracellular volume. Here, we have demonstrated that urine concentration, and therefore regulation of water conservation, is an important control system for urine formation and extracellular volume homeostasis in mice and humans across various levels of salt intake. We observed that the renal concentration mechanism couples natriuresis with correspondent renal water reabsorption, limits natriuretic osmotic diuresis, and results in concurrent extracellular volume conservation and concentration of salt excreted into urine. This water-conserving mechanism of dietary salt excretion relies on urea transporter-driven urea recycling by the kidneys and on urea production by liver and skeletal muscle. The energy-intense nature of hepatic and extrahepatic urea osmolyte production for renal water conservation requires reprioritization of energy and substrate metabolism in liver and skeletal muscle, resulting in hepatic ketogenesis and glucocorticoid-driven muscle catabolism, which are prevented by increasing food intake. This natriuretic-ureotelic, water-conserving principle relies on metabolism-driven extracellular volume control and is regulated by concerted liver, muscle, and renal actions.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Cloreto de Sódio na Dieta/farmacologia , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Animais , Rim/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Músculo Esquelético/metabolismo , Sódio/urina , Ureia/metabolismo
19.
Res Microbiol ; 157(1): 5-12, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16364606

RESUMO

The International Space Station (ISS) is an orbital living and working environment extending from the original Zarya control module built in 1998. The expected life span of the completed station is around 10 years and during this period it will be constantly manned. It is inevitable that the ISS will also be home to an unknown number of microorganisms. This survey reports on microbiological contamination in potable water, air, and on surfaces inside the ISS. The viable counts in potable water did not exceed 1.0 x 10(2) CFU/ml. Sphingomonas sp. and Methylobacterium sp. were identified as the dominant genera. Molecular analysis demonstrated the presence of nucleic acids belonging to various pathogens, but no viable pathogens were recovered. More than 500 samples were collected at different locations over a period of 6 years to characterize air and surface contamination in the ISS. Concentrations of airborne bacteria and fungi were lower than 7.1 x 10(2) and 4.4 x 10(1) CFU/m3, respectively. Staphylococcus sp. was by far the most dominant airborne bacterial genus, whereas Aspergillus sp. and Penicillium sp. dominated the fungal population. The bacterial concentrations in surface samples fluctuated from 2.5 x 10(1) to 4.3 x 10(4) CFU/100 cm2. Staphylococcus sp. dominated in all of these samples. The number of fungi varied between 2.5 x 10(1) and 3.0 x 10(5) CFU/100 cm2, with Aspergillus sp. and Cladosporium sp. as the most dominant genera. Furthermore, the investigations identified the presence of several (opportunistic) pathogens and strains involved in the biodegradation of structural materials.


Assuntos
Microbiologia do Ar , Poluição do Ar em Ambientes Fechados , Sistemas Ecológicos Fechados , Voo Espacial , Bactérias/classificação , Bactérias/crescimento & desenvolvimento , Coleta de Dados , Monitoramento Ambiental , Fungos/classificação , Fungos/crescimento & desenvolvimento , Astronave
20.
Am J Clin Nutr ; 104(1): 49-57, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27225435

RESUMO

BACKGROUND: The intake of sodium, chloride, and potassium is considered important to healthy nutrition and cardiovascular disease risk. Estimating the intake of these electrolytes is difficult and usually predicated on urine collections, commonly for 24 h, which are considered the gold standard. We reported on data earlier for sodium but not for potassium or chloride. OBJECTIVE: We were able to test the value of 24-h urine collections in a unique, ultra-long-term balance study conducted during a simulated trip to Mars. DESIGN: Four healthy men were observed while ingesting 12 g salt/d, 9 g salt/d, and 6 g salt/d, while their potassium intake was maintained at 4 g/d for 105 d. Six healthy men were studied while ingesting 12 g salt/d, 9 g salt/d, and 6 g salt/d, with a re-exposure of 12 g/d, while their potassium intake was maintained at 4 g/d for 205 d. Food intake and other constituents were recorded every day for each subject. All urine output was collected daily. RESULTS: Long-term urine recovery rates for all 3 electrolytes were very high. Rather than the expected constant daily excretion related to daily intake, we observed remarkable daily variation in excretion, with a 7-d infradian rhythm at a relatively constant intake. We monitored 24-h aldosterone excretion in these studies and found that aldosterone appeared to be the regulator for all 3 electrolytes. We report Bland-Altman analyses on the value of urine collections to estimate intake. CONCLUSIONS: A single 24-h urine collection cannot predict sodium, potassium, or chloride intake; thus, multiple collections are necessary. This information is important when assessing electrolyte intake in individuals.


Assuntos
Dieta , Eletrólitos/urina , Ritmo Infradiano , Potássio/urina , Cloreto de Sódio na Dieta/urina , Sódio/urina , Equilíbrio Hidroeletrolítico , Adulto , Aldosterona/urina , Eletrólitos/administração & dosagem , Humanos , Estudos Longitudinais , Masculino , Potássio/administração & dosagem , Sódio/administração & dosagem , Cloreto de Sódio na Dieta/administração & dosagem
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