Participación de los canales de cloruro en la salud cardiovascular y renal. Efectos de dietas altas en cloro sobre la presión arterial en un modelo experimental de sobrecarga salina / Participation of Chloride Channels in Cardiovascular and Kidney Health. Effects of High Chloride Diets on Blood Pressure in an Experimental Model of Saline Overload

RESUMEN Introducción . El consumo excesivo de sal (cloruro de sodio, NaCl) en la dieta conduce al desarrollo de hipertensión arterial (HTA) y daño de órgano blanco. Se sabe que los canales ClC-K1 y ClC-5 son reguladores esenciales del anión cloruro (Cl-), pero la contribución de este anión a los efectos deletéreos de la sal es aún desconocida. Objetivo . El objetivo de este trabajo fue evaluar la participación del Cl- en la respuesta inflamatoria y oxidativa renal y en el desarrollo de HTA. Material y métodos . Ratas Wistar macho se dividieron en cuatro grupos (n=8/grupo) y se alimentaron con diferentes dietas durante 3 semanas. control (grupo C); NaCl 8 % (grupo NaCl); dieta alta en Na+. citrato de sodio (Na3C6H5O7) 11,8 % (grupo Na); dieta alta en Cl-. cloruro de calcio (CaCl2) 3,80 %, cloruro de potasio (KCl) 3,06 % y cloruro de magnesio (MgCl2) 1,30 % (grupo Cl). Se determinó la presión arterial sistólica (PAS), función renal, marcadores de estrés oxidativo y de inflamación en corteza renal, y la expresion renal de los canales de cloruro ClC-K1 y ClC-5. Resultados . Se observó un aumento de la PAS, actividad de glutatión peroxidasa (GPx) y expresión renal de factor nuclear kappa B (NFkB) y receptor de angiotensina II tipo 1 (AT1R) en los grupos NaCl y Cl- (p<0,05). La producción de sustancias reactivas del ácido tiobarbitúrico (TBARS) aumentó en los grupos experimentales con respecto a C. La expresión de la proteína de Parkinson 7 (PARK7) disminuyó en el grupo Cl en comparación con C (p< 0,05). Los grupos NaCl y Cl- mostraron una mayor expresión de ClC-K1, mientras que ClC-5 se redujo en el grupo NaCl en comparación con C (p<0,05). Conclusión . El Cl- sería corresponsable, junto con el Na+, de desencadenar daño oxidativo e inflamatorio renal y aumentar la presión arterial; por ello se deduce la importancia de reducir la ingesta de ambos iones como medida preventiva no farmacológica para la prevención y control de la HTA. El rol de los canales ClC-K1 y ClC-5 como mediadores de este proceso queda aún por confirmarse.

ABSTRACT Background . Excessive consumption of salt (sodium chloride, NaCl) in the diet leads to the development of hypertension (HTN) and target organ damage. It is known that the ClC-K1 and ClC-5 channels are essential regulators of the chloride (Cl-) anion, but the contribution of this anion to salt-harmful effects remains unknown. Objective . The aim of this study was to evaluate the participation of Cl- in the renal inflammatory and oxidative response and in the development of HTN. Methods . Male Wistar rats were divided into four groups (n=8/group) and fed with different diets for 3 weeks. control (C group); NaCl 8% (NaCl group); high Na+ diet. sodium citrate (Na3C6H5O7) 11.8% (Na group); high Cl- diet. calcium chloride (CaCl2) 3.80%, potassium chloride (KCl) 3.06% and magnesium chloride (MgCl2) 1.30% (Cl group). Systolic blood pressure (SBP), renal function, oxidative stress and inflammation markers in the renal cortex, and renal expression of the chloride ClC-K1 and ClC-5 channels were assessed. Results . An increase in SBP, glutathione peroxidase (GPx) activity, and renal expression of nuclear factor kappa B (NFkB) and angiotensin II type 1 receptor (AT1R) were observed in the NaCl and Cl groups (p<0.05). The production of thiobarbituric acid reactive substances (TBARS) increased in the experimental groups compared with C. The expression of Parkinson disease protein 7 (PARK7) decreased in the Cl group compared with C (p< 0.05). The NaCl and Cl groups showed increased expression of ClC-K1, while ClC-5 was reduced in the NaCl group compared with C (p<0.05) Conclusion . Cl- would be co-responsible together with Na+ in triggering oxidative and inflammatory kidney damage and increasing blood pressure. This indicates the importance of reducing the intake of both ions as a non-pharmacological preventive measure for the prevention and control of HTN. The role of ClC-K1 and ClC-5 channels as mediators of this process remains to be confirmed.

Controversias en el uso de la vitamina D como preventivo de la esclerosis múltiple. Revisión de la literatura / Controversies in the use of vitamin D as a preventive of multiple sclerosis. Literature review

La esclerosis múltiple (EM) es una enfermedad desmielinizante que afecta el sistema nervioso central. A pesar de los avances en materia de diagnóstico y tratamiento, se desconocen aún muchos aspectos de su etiopatogenia y fisiopatología. La EM es una de las principales causas de discapacidad neurológica y, por los elevados costos de los tratamientos inmunomoduladores e inmunosupresores, tiene un gran impacto económico en la salud pública. Por ello, se intentaron diversos tratamientos preventivos, como la utilización de la vitamina D. Debido a la acción de la vitamina D sobre el sistema inmune, ha sido prescripta en sujetos de riesgo. Sin embargo, hasta el momento actual, los estudios sobre sus efectos no resultaron concluyentes y persisten las dudas acerca de sus posibles beneficios en materia de prevención. El objetivo de la presente revisión bibliográfica es realizar una puesta al día y destacar los aspectos controversiales en relación al uso de la vitamina D como tratamiento preventivo de la esclerosis múltiple. (AU)

Multiple sclerosis (MS) is a demyelinating disease that affects the central nervous system. Despite advances in diagnosis and treatment, many aspects of its etiopathogenesis and pathophysiology remain unknown. MS is one of the main causes of neurological disability and, due to the high costs of modern immunomodulatory and immunosuppressive treatments, it has a great economic impact on public health. Therefore, numerous efforts have been made in the search for preventive treatments. For this reason, various preventive treatments were tried, such as the use of vitamin D. Due to its action on the immune system, it has been used in subjects at ME risk. However, these studies have been inconclusive to date, and its possible benefits in terms of prevention are still being questioned. The objective of this bibliographic review is to update and highlight the controversial aspects in relation to the use of vitamin D as a preventive treatment of multiple sclerosis. (AU)

Clues and new evidences in arterial hypertension: unmasking the role of the chloride anion.

The present review will focus on the role of chloride anion in cardiovascular disease, with special emphasis in the development of hypertensive disease and vascular inflammation. It is known that acute and chronic overload of sodium chloride increase blood pressure and have pro-inflammatory and pro-fibrotic effects on different target organs, but it is unknown how chloride may influence these processes. Chloride anion is the predominant anion in the extracellular fluid and its intracellular concentration is dynamically regulated. As the queen of the electrolytes, it is of crucial importance to understand the physiological mechanisms that regulate the cellular handling of this anion including the different transporters and cellular chloride channels, which exert a variety of functions, such as regulation of cellular proliferation, differentiation, migration, apoptosis, intracellular pH and cellular redox state. In this article, we will also review the relationship between dietary, serum and intracellular chloride and how these different sources of chloride in the organism are affected in hypertension and their impact on cardiovascular disease. Additionally, we will discuss the approach of potential strategies that affect chloride handling and its potential effect on cardiovascular system, including pharmacological blockade of chloride channels and non-pharmacological interventions by replacing chloride by another anion.

Role of natriuretic peptides in the cardiovascular-adipose communication: a tale of two organs.

Natriuretic peptides have long been known for their cardiovascular function. However, a growing body of evidence emphasizes the role of natriuretic peptides in the energy metabolism of several substrates in humans and animals, thus interrelating the heart, as an endocrine organ, with various insulin-sensitive tissues and organs such as adipose tissue, muscle skeletal, and liver. Adipose tissue dysfunction is associated with altered regulation of the natriuretic peptide system, also indicated as a natriuretic disability. Evidence points to a contribution of this natriuretic disability to the development of obesity, type 2 diabetes mellitus, and cardiometabolic complications; although the causal relationship is not fully understood at present. However, targeting the natriuretic peptide pathway may improve metabolic health in obesity and type 2 diabetes mellitus. This review will focus on the current literature on the metabolic functions of natriuretic peptides with emphasis on lipid metabolism and insulin sensitivity. Natriuretic peptide system alterations could be proposed as one of the linking mechanisms between adipose tissue dysfunction and cardiovascular disease.

Protective Renal Effects of Atrial Natriuretic Peptide: Where Are We Now?

Atrial natriuretic peptide belongs to the family of natriuretic peptides, a system with natriuretic, diuretic, and vasodilator effects that opposes to renin-angiotensin system. In addition to its classic actions, atrial natriuretic peptide exerts a nephroprotective effect given its antioxidant and anti-inflammatory properties, turning it as a beneficial agent against acute and chronic kidney diseases. This minireview describes the most relevant aspects of atrial natriuretic peptide in the kidney, including its renal synthesis, physiological actions through specific receptors, the importance of its metabolism, and its potential use in different pathological scenarios.

Cardiac Natriuretic Peptide Profiles in Chronic Hypertension by Single or Sequentially Combined Renovascular and DOCA-Salt Treatments.

The involvement of natriuretic peptides was studied during the hypertrophic remodeling transition mediated by sequential exposure to chronic hemodynamic overload. We induced hypertension in rats by pressure (renovascular) or volume overload (DOCA-salt) during 6 and 12 weeks of treatment. We also studied the consecutive combination of both models in inverse sequences: RV 6 weeks/DS 6 weeks and DS 6 weeks/RV 6 weeks. All treated groups developed hypertension. Cardiac hypertrophy and left ventricular ANP gene expression were more pronounced in single DS than in single RV groups. BNP gene expression was positively correlated with left ventricular hypertrophy only in RV groups, while ANP gene expression was positively correlated with left ventricular hypertrophy only in DS groups. Combined models exhibited intermediate values between those of single groups at 6 and 12 weeks. The latter stimulus associated to the second applied overload is less effective than the former to trigger cardiac hypertrophy and to increase ANP and BNP gene expression. In addition, we suggest a correlation of ANP synthesis with volume overload and of BNP synthesis with pressure overload-induced hypertrophy after a prolonged treatment. Volume and pressure overload may be two mechanisms, among others, involved in the differential regulation of ANP and BNP gene expression in hypertrophied left ventricles. Plasma ANP levels reflect a response to plasma volume increase and volume overload, while circulating BNP levels seem to be regulated by cardiac BNP synthesis and ventricular hypertrophy.

Hacia el esclarecimiento del rol del anión cloruro en la hipertensión arterial: / Towards the Elucidation of the Role of the Chloride Anion in Arterial Hypertension:

RESUMEN Introducción: Se desconoce el papel del anión cloruro en los efectos deletéreos del consumo excesivo de sal (NaCl) y si sus efectos son independientes de la presencia del sodio. Objetivo: Demostrar que tanto una sobrecarga de cloruro como una sobrecarga de sodio en la dieta producen efectos deletéreos, en forma independiente, sobre la presión arterial sistólica (PAS), la función renal y los marcadores de estrés oxidativo en el riñón. Materiales y métodos: Ratas Wistar macho fueron divididas en cuatro grupos (n = 8/grupo) y fueron alimentadas con diferentes dietas durante tres semanas: C: control (dieta estándar), NaCl: hipersódica-hiperclórica, Na: hipersódica sin cloruro, Cl: hiperclórica sin sodio. Se determinaron la presión arterial sistólica (PAS) y la función renal y en la corteza renal, se evaluó la producción de especies reactivas del ácido tiobarbitúrico (en inglés: TBARS) y la actividad y la expresión de las enzimas superóxido dismutasa (SOD), catalasa (CAT) y glutatión peroxidasa (GPx). Resultados: Al cabo de tres semanas, la PAS aumentó (*) en los dos grupos alimentados con cloruro. La excreción fraccional de sodio y de cloruro aumentó (*) en los grupos NaCl y Na. La diuresis y los TBARS en la corteza renal aumentaron (*) con las tres dietas, sin cambios en la actividad y en la expresión de SOD y CAT. La actividad de la GPx aumentó (*) en los dos grupos que recibieron cloruro; (*p < 0,05 vs C). Conclusión: Tanto la sobrecarga de sodio como la de cloruro se asocian a mayor estado oxidativo caracterizado por un incremento en la peroxidación lipídica en la corteza renal. Sin embargo, solo el exceso de cloruro se asocia a mayor actividad de la GPx y de la hipertensión, sin cambios en la excreción urinaria de cloruros, sugiriendo un mayor estado prooxidante renal en comparación con el grupo Na.

ABSTRACT Introduction: The role of the chloride anion on the deleterious effects of excessive consumption of salt (NaCl) and whether its effects are independent each other of the presence of sodium remains to date, unknown and unclear. Objective: To demonstrate that both a chloride overload and a sodium overload in the diet produce deleterious effects, by different mechanisms, on systolic blood pressure (SBP), renal function and markers of oxidative stress in the kidney. Materials and Methods: Male Wistar rats were divided into four groups (n = 8 / group) and fed with different diets for three weeks: C: control (standard diet), and diets: NaCl: hypersodic-hyperchloric; Na: hypersodic without chloride and Cl: hyperchloric without sodium. Systolic blood pressure (SBP) and renal function were determined, and the production of thiobarbituric acid reactive species (TBARS) and the activity and expression of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) enzymes were evaluated in renal cortex tissue. Results: SBP increased (*) in the two groups fed with chloride. The fractional excretion of sodium and chloride increased (*) in the NaCl and Na groups. increased (*) in the renal cortex with the three diets. No changes were observed in the activity and expression of SOD and CAT. GPx activity increased (*) in the two groups that received chloride; (* p <0.05 vs C). Conclusion: Both sodium and chloride overload are associated with a higher oxidative state characterized by an increase in lipid peroxidation in the renal cortex. However, compared with Na group, only chloride overload is associated with higher GPx activity and hypertension without any changes in urinary chloride excretion, suggesting a higher renal pro-oxidant state in this experimental group.

Acute infusion of angiotensin II regulates organic cation transporters function in the kidney: its impact on the renal dopaminergic system and sodium excretion.

A close relationship between angiotensin II (ANG II) and the renal dopaminergic system (RDS) has been reported. Our aim was to study whether renal dopamine and ANG II can interact to modify renal sodium handling and then to elucidate the related mechanism. Anesthetized male Sprague-Dawley rats were used in experiments. ANG II, exogenous dopamine, and decynium-22 (or D-22, an isocyanine that specifically blocks electrogenic organic cation transporters, OCTs), were infused in vivo for 120 min. We analyzed renal and hemodynamic parameters, renal Na+, K+-ATPase levels, OCT activity, and urinary dopamine concentrations. We also evaluated the expression of D1 receptor, electroneutral organic cation transporters (OCTNs), and OCTs. ANG II decreased renal excretion of sodium in the presence of exogenous dopamine, increased Na+, K+-ATPase activity, and decreased the urinary dopamine concentration. D-22 treatment exacerbated the ANG II-mediated decrease in renal excretion of sodium and dopamine urine excretion but did not modify ANG II stimulation of Na+, K+-ATPase activity. The infusion of ANG II did not affect the expression of D1 receptor, OCTs, or OCTNs. However, the activity of OCTs was diminished by the presence of ANG II. Although ANG II did not alter the expression of D1 receptor, OCTs, and OCTNs in renal tissues, it modified the activity of OCTs and thereby decreased the urinary dopamine concentration, showing a novel mechanism by which ANG II decreases dopamine transport and its availability in the tubular lumen to stimulate D1 receptor. This study demonstrates a relationship between ANG II and dopamine, where both agents counteract their effects on sodium excretion.

Alteration of Renal Natriuretic Systems Is Associated with the Development of Hypertension and Precedes the Presence of Renal Damage in a Model of Metabolic Syndrome / La alteración de sistemas natriuréticos renales se asocia con el desarrollo de hipertensión arterial y precede en el tiempo a la aparición de daño renal en un modelo de síndrome metabólico

ABSTRACT: Background: The aim of this study was to determine the presence of alterations in the natriuretic systems of atrial natriuretic peptide and renal dopamine in a model of metabolic syndrome induced by fructose overload and to associate them with changes in systolic blood pressure, renal function, Na+/K+-ATPase status and microalbuminuria. Methods: Male Sprague-Dawley rats were divided into control (C) and fructose (F) groups receiving drinking water or a fructose so-lution (10% W/V), respectively, for 4, 8 and 12 weeks. L-dopa and dopamine, sodium, creatinine and albumin were measured in urine and ANP, insulin, sodium and creatinine in plasma. Systolic blood pressure was measured by indirect method and the renal activity and expression of Na+/K+-ATPase as well as the renal expression of A- and C-type natriuretic peptide receptors were assessed. results: Fructose overload was associated with a significant increase in insulinemia and systolic blood pressure levels and a decrease in urinary sodium excretion since week 4. A significant increase in L-dopa excretion and a decrease in dopamine excretion (increased urinary L-dopa/dopamine ratio) due to fructose overload were observed since week 4 with a decrease in plasma atrial natriuretic peptide at weeks 8 and 12. These changes were accompanied by increased activity and expression of Na+/ K+-ATPase, decreased A-type natriuretic peptide receptor and increased C-type natriuretic peptide receptor expression. Microalbuminuria was observed at week 12 of fructose overload.

RESUMEN: Objetivos: El objetivo del trabajo consistió en determinar la existencia de alteraciones en los sistemas natriuréticos del péptido natriurético atrial y dopamina renal en un modelo de síndrome metabólico por sobrecarga de fructosa y asociarlas con cambios en la presión arterial sistólica, función renal, estado de la Na+, K+-ATPasa y microalbuminuria. Material y Métodos: Ratas macho Sprague-Dawley fueron divididas en grupos control (C) y fructosa (F) con agua o solución de F (10%P/V) para beber durante 4, 8 y 12 semanas. En orina, se midió L-dopa y dopamina, sodio, creatinina y albúmina; y en plasma péptido natriurético atrial, insulina, sodio y creatinina. La presión arterial sistólica fue medida por método indirecto. Se midió la actividad y expresión de la Na+, K+-ATPasa así como la expresión del receptor de péptidos natriuréticos A y C renales. resultados: La sobrecarga de fructosa se asoció con el aumento de la insulinemia y la presión arterial sistólica, y con la disminución en la excreción urinaria de sodio desde la semana 4. La excreción urinaria de L-dopa se incrementó y la de dopamina disminuyó (cociente L-dopa/dopamina incrementado) por sobrecarga de fructosa desde la semana 4 y el péptido natriurético atrial plasmático se redujo en las semanas 8 y 12. Estos cambios fueron acompañados por un incremento de la actividad y expresión de la Na+, K+-ATPasa, disminución del receptor de péptidos natriuréticos A y aumento del C. La microalbuminuria se observó en la semana 12 de sobrecarga de fructosa. Conclusiones: Las alteraciones del péptido natriurético atrial y de la dopamina renal se asociaron con el desarrollo de hipertensión arterial y precedieron a la aparición de microalbuminuria, por lo que se pudo establecer una asociación temporal entre la alteración de ambos sistemas y el desarrollo de daño renal.

Short-term effects of a green coffee extract-, Garcinia c ambogia- and L-carnitine-containing chewing gum on snack intake and appetite regulation.

INTRODUCTION: Different studies have assessed the influence of chewing gum to aid control of appetite and reduce food intake. PURPOSE: The aims of the present study were to evaluate the effects of chewing gum on satiety, food hedonics and snack intake and to explore the potential effects of the combination of Garcinia c ambogia, green coffee extract and L-carnitine on satiety, when administered in a gum format. METHODS: This was a prospective study in which 57 subjects randomly received three kinds of treatments, in a crossover design: (1) active gum; (2) placebo gum; and (3) no gum. Food preferences and appetite sensations were evaluated by means of the Leeds Food Preference Questionnaire and visual analog scales. RESULTS: There was a significant reduction in low-fat sweet snack intake with placebo gum and the active gum compared to no gum and a reduction in high-fat sweet snack intake with the active gum compared to placebo gum and no gum. Total caloric intake was only reduced in the active gum condition. Both the active and placebo gum conditions significantly reduced hunger and prospective food consumption and increased fullness compared to no gum and were associated with a reduced wanting for sweet food in the LFPQ, consistent in a reduction in the relative preference for sweet snacks versus savoury snacks. CONCLUSION: This study supports the notion that chewing gum containing nutraceutical products might aid in the control over snack intake and reduce hunger sensations.

Immunohistochemical expression of intrarenal renin angiotensin system components in response to tempol in rats fed a high salt diet.

AIM: To determine the effect of tempol in normal rats fed high salt on arterial pressure and the balance between antagonist components of the renal renin-angiotensin system. METHODS: Sprague-Dawley rats were fed with 8% NaCl high-salt (HS) or 0.4% NaCl (normal-salt, NS) diet for 3 wk, with or without tempol (T) (1 mmol/L, administered in drinking water). Mean arterial pressure (MAP), glomerular filtration rate (GFR), and urinary sodium excretion (UVNa) were measured. We evaluated angiotensin II (Ang II), angiotensin 1-7 (Ang 1-7), angiotensin converting enzyme 2 (ACE2), mas receptor (MasR), angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptor (AT2R) in renal tissues by immunohistochemistry. RESULTS: The intake of high sodium produced a slight but significant increase in MAP and differentially regulated components of the renal renin-angiotensin system (RAS). This included an increase in Ang II and AT1R, and decrease in ACE-2 staining intensity using immunohistochemistry. Antioxidant supplementation with tempol increased natriuresis and GFR, prevented changes in blood pressure and reversed the imbalance of renal RAS components. This includes a decrease in Ang II and AT1R, as increase in AT2, ACE2, Ang (1-7) and MasR staining intensity using immunohistochemistry. In addition, the natriuretic effects of tempol were observed in NS-T group, which showed an increased staining intensity of AT2, ACE2, Ang (1-7) and MasR. CONCLUSION: These findings suggest that a high salt diet leads to changes in the homeostasis and balance between opposing components of the renal RAS in hypertension to favour an increase in Ang II. Chronic antioxidant supplementation can modulate the balance between the natriuretic and antinatriuretic components of the renal RAS.

Atrial Natriuretic Peptide Stimulates Dopamine Tubular Transport by Organic Cation Transporters: A Novel Mechanism to Enhance Renal Sodium Excretion.

The aim of this study was to demonstrate the effects of atrial natriuretic peptide (ANP) on organic cation transporters (OCTs) expression and activity, and its consequences on dopamine urinary levels, Na+, K+-ATPase activity and renal function. Male Sprague Dawley rats were infused with isotonic saline solution during 120 minutes and randomized in nine different groups: control, pargyline plus tolcapone (P+T), ANP, dopamine (DA), D-22, DA+D-22, ANP+D-22, ANP+DA and ANP+DA+D-22. Renal functional parameters were determined and urinary dopamine concentration was quantified by HPLC. Expression of OCTs and D1-receptor in membrane preparations from renal cortex tissues were determined by western blot and Na+, K+-ATPase activity was determined using in vitro enzyme assay. 3H-DA renal uptake was determined in vitro. Compared to P+T group, ANP and dopamine infusion increased diuresis, urinary sodium and dopamine excretion significantly. These effects were more pronounced in ANP+DA group and reversed by OCTs blockade by D-22, demonstrating that OCTs are implied in ANP stimulated-DA uptake and transport in renal tissues. The activity of Na+, K+-ATPase exhibited a similar fashion when it was measured in the same experimental groups. Although OCTs and D1-receptor protein expression were not modified by ANP, OCTs-dependent-dopamine tubular uptake was increased by ANP through activation of NPR-A receptor and protein kinase G as signaling pathway. This effect was reflected by an increase in urinary dopamine excretion, natriuresis, diuresis and decreased Na+, K+-ATPase activity. OCTs represent a novel target that links the activity of ANP and dopamine together in a common mechanism to enhance their natriuretic and diuretic effects.

Renal dopaminergic system: Pathophysiological implications and clinical perspectives.

Fluid homeostasis, blood pressure and redox balance in the kidney are regulated by an intricate interaction between local and systemic anti-natriuretic and natriuretic systems. Intrarenal dopamine plays a central role on this interactive network. By activating specific receptors, dopamine promotes sodium excretion and stimulates anti-oxidant and anti-inflammatory pathways. Different pathological scenarios where renal sodium excretion is dysregulated, as in nephrotic syndrome, hypertension and renal inflammation, can be associated with impaired action of renal dopamine including alteration in biosynthesis, dopamine receptor expression and signal transduction. Given its properties on the regulation of renal blood flow and sodium excretion, exogenous dopamine has been postulated as a potential therapeutic strategy to prevent renal failure in critically ill patients. The aim of this review is to update and discuss on the most recent findings about renal dopaminergic system and its role in several diseases involving the kidneys and the potential use of dopamine as a nephroprotective agent.

Atrial natriuretic peptide and renal dopaminergic system: a positive friendly relationship?

Sodium metabolism by the kidney is accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Renal dopamine plays a central role in this interactive network. The natriuretic hormones, such as the atrial natriuretic peptide, mediate some of their effects by affecting the renal dopaminergic system. Renal dopaminergic tonus can be modulated at different steps of dopamine metabolism (synthesis, uptake, release, catabolism, and receptor sensitization) which can be regulated by the atrial natriuretic peptide. At tubular level, dopamine and atrial natriuretic peptide act together in a concerted manner to promote sodium excretion, especially through the overinhibition of Na+, K+-ATPase activity. In this way, different pathological scenarios where renal sodium excretion is dysregulated, as in nephrotic syndrome or hypertension, are associated with impaired action of renal dopamine and/or atrial natriuretic peptide, or as a result of impaired interaction between these two natriuretic systems. The aim of this review is to update and comment on the most recent evidences demonstrating how the renal dopaminergic system interacts with atrial natriuretic peptide to control renal physiology and blood pressure through different regulatory pathways.

Renal overexpression of atrial natriuretic peptide and hypoxia inducible factor-1α as adaptive response to a high salt diet.

In the kidney, a high salt intake favors oxidative stress and hypoxia and causes the development of fibrosis. Both atrial natriuretic peptide (ANP) and hypoxia inducible factor (HIF-1α) exert cytoprotective effects. We tested the hypothesis that renal expression of ANP and HIF-1α is involved in a mechanism responding to the oxidative stress produced in the kidneys of rats chronically fed a high sodium diet. Sprague-Dawley rats were fed with a normal salt (0.4% NaCl) (NS) or a high salt (8% NaCl) (HS) diet for 3 weeks, with or without the administration of tempol (T), an inhibitor of oxidative stress, in the drinking water. We measured the mean arterial pressure (MAP), glomerular filtration rate (GFR), and urinary sodium excretion (UVNa). We evaluated the expression of ANP, HIF-1α, and transforming growth factor (TGF-ß1) in renal tissues by western blot and immunohistochemistry. The animals fed a high salt diet showed increased MAP and UVNa levels and enhanced renal immunostaining of ANP, HIF-1α, and TGF-ß1. The administration of tempol together with the sodium overload increased the natriuresis further and prevented the elevation of blood pressure and the increased expression of ANP, TGF-ß1, and HIF-1α compared to their control. These findings suggest that HIF-1α and ANP, synthesized by the kidney, are involved in an adaptive mechanism in response to a sodium overload to prevent or attenuate the deleterious effects of the oxidative stress and the hypoxia on the development of fibrosis.

Evaluation of the satiating properties of a nutraceutical product containing Garcinia cambogia and Ascophyllum nodosum extracts in healthy volunteers.

A nutraceutical product composed of a combination of Garcinia cambogia, l-carnitine and a seaweed extract of Ascophyllum nodosum has been recently developed. The aim of the present study was to characterize its effects on subjective satiety sensations and food preferences in healthy volunteers. In a crossover design, 28 subjects (21 females and 7 males, aged 31 ± 5, BMI 22.6 ± 1.7) were randomly assigned to receive the active treatment (LIS) or placebo (PL) over one week. At the end of each treatment period, subjects were instructed to consume ad libitum a test meal. Food preferences and appetite sensations were evaluated by means of the Leeds Food Preferences Questionnaire and visual analog scales, before and after meal, over three hours. There were no differences in energy intake between study groups. LIS was associated with a reduction in subjective hunger sensations (p = 0.018) and to an increase in satiety (p = 0.02) and fullness (p = 0.01) ratings. The preference for high fat foods was reduced after consuming the test meal in both study groups. There was a significant effect of LIS treatment on food explicit liking and implicit wanting, as evidenced by an increase in preference for sweet foods (relative to savory foods; p = 0.03 and p = 0.004, respectively), but no differences were observed regarding the preference for low or high fat foods (NS). These results provide proof of principle for the satiating properties of a nutraceutical containing Garcinia cambogia, Ascophyllum nodosum extract and l-carnitine and suggest that it might be useful as an appetite modulator.

Salt-induced downregulation of renal aquaporins is prevented by losartan.

AIMS: The purpose of this study was to investigate the expression of aquaporin-1 (AQP-1) and aquaporin-2 (AQP-2) in the renal tubule of rats fed with a high-salt diet and its modulation by the AT1 receptor blocker losartan. MAIN METHODS: The experiments were performed in four groups of rats fed for 3 weeks with the following diets: regular rat chow (NS); high-salt (8% NaCl) chow (HS), NS plus losartan (NS-L) and HS plus losartan (HS-L). Losartan (40 mg x kg(-1)) was administered in the drinking water. Systolic blood pressure (SBP) and renal function were evaluated. The intrarenal levels of angiotensin II (Ang II), TGF-ß(1), α-smooth muscle actin (α-SMA), endothelial nitric oxide synthase (eNOS), AQP-1 and AQP-2 were determined by immunohistochemistry. AQP-1 and AQP-2 protein levels were measured by western blot analysis. KEY FINDINGS: A high-sodium diet downregulated AQP-1 and AQP-2 expression levels in the proximal tubule and collecting duct, respectively. The high-sodium diet also induced Ang II, TGF-ß(1) and α-SMA overexpression and decreased eNOS expression in the renal cortex and medulla. Losartan increased the diuresis and natriuresis, favoring urinary sodium concentration. Additionally, losartan prevented the profibrogenic response, decreasing Ang II, TGF-ß(1) and α-SMA levels and normalizing AQP-2 expression in the HS-L group. AQP-1 expression was upregulated by losartan in both the NS-L and HS-L groups. SIGNIFICANCE: These results show that increased intrarenal Ang II in rats fed with a high-salt diet downregulates renal AQP-1 and AQP-2 expressions. In addition, although losartan increased diuresis and natriuresis, it prevented the downregulation of aquaporins, favoring urinary sodium concentration.

Angiotensin-(1-7) through Mas receptor up-regulates neuronal norepinephrine transporter via Akt and Erk1/2-dependent pathways.

As angiotensin (Ang) (1-7) decreases norepinephrine (NE) content in the synaptic cleft, we investigated the effect of Ang-(1-7) on NE neuronal uptake in spontaneously hypertensive rats. [(3)H]-NE neuronal uptake was measured in isolated hypothalami. NE transporter (NET) expression was evaluated in hypothalamic neuronal cultures by western-blot. Ang-(1-7) lacked an acute effect on neuronal NE uptake. Conversely, Ang-(1-7) caused an increase in NET expression after 3 h incubation (40 ± 7%), which was blocked by the Mas receptor antagonist, a PI3-kinase inhibitor or a MEK1/2 inhibitor suggesting the involvement of Mas receptor and the PI3-kinase/Akt and MEK1/2-ERK1/2 pathways in the Ang-(1-7)-stimulated NET expression. Ang-(1-7) through Mas receptors stimulated Akt and ERK1/2 activities in spontaneously hypertensive rat neurons. Cycloheximide attenuated Ang-(1-7) stimulation of NET expression suggesting that Ang-(1-7) stimulates NET synthesis. In fact, Ang-(1-7) increased NET mRNA levels. Thus, we evaluated the long-term effect of Ang-(1-7) on neuronal NE uptake after 3 h incubation. Under this condition, Ang-(1-7) increased neuronal NE uptake by 60 ± 14% which was blocked by cycloheximide and the Mas receptor antagonist. Neuronal NE uptake and NET expression were decreased after 3 h incubation with an anti-Ang-(1-7) antibody. Ang-(1-7) induces a chronic stimulatory effect on NET expression. In this way, Ang-(1-7) may regulate a pre-synaptic mechanism in maintaining appropriate synaptic NE levels during hypertensive conditions.

Perfiles de síntesis y secreción de los péptidos natriuréticos durante la evolución de la hipertrofia cardíaca en ratas hipertensas DOCA-sal / Natriuretic Peptides Synthesis and Secretion Profiles during the Evolution of Cardiac Hypertrophy in DOCA-Salt Hypertensive Rats / Natriuretic Peptides Synthesis and Secretion Profiles during the Evolution of Cardiac Hypertrophy in DOCASalt Hypertensive Rats

Durante el desarrollo de la hipertensión arterial, las interacciones entre las sobrecargas de presión y de volumen conducen a diferentes patrones de hipertrofia cardíaca y a un aumento de los péptidos natriuréticos (PN). Los perfiles de síntesis y secreción de ANP y BNP se han investigado en modelos de hipertensión arterial; sin embargo, aún no se ha estudiado la evolución diferencial de estos perfiles durante períodos agudos y crónicos de la hipertrofia cardíaca producida por sobrecarga de volumen. Por este motivo estudiamos ratas Sprague- Dawley con el modelo DOCA-sal a las 2, 4, 6 y 12 semanas, correlacionando la evolución de dichos perfiles con la hipertrofia cardíaca y la hipertensión arterial. El grado de hipertrofia cardíaca se correlacionó positivamente con la expresión del ANP en el ventrículo izquierdo y con los niveles de ANP en plasma. La expresión del ANP aumentó a las 4 semanas de tratamiento, mientras que la de BNP se incrementó recién a las 6 semanas. Asimismo, el BNP plasmático se incrementó sólo en el grupo con 12 semanas de tratamiento, mientras que el ANP plasmático mostró un aumento a partir de las 2 semanas de tratamiento. Durante el desarrollo de la hipertrofia cardíaca producida en el modelo DOCA-sal, la síntesis y la secreción de los PN responden en forma diferencial, con incremento precoz del ANP. Además, el aumento de éste superó al de BNP en todos los grupos DOCA-sal, lo que permitiría considerar al ANP como un marcador más específico de la sobrecarga de volumen.

The interactions between pressure and volume overload that occur in hypertension lead to different patterns of cardiac hypertrophy and to increase in natriuretic peptides (NPs). The profiles of ANP and BNP synthesis and secretion have been investigated in models of hypertension; however, the different evolution of these profiles during the acute and chronic periods of pressure overload-induced cardiac hypertrophy is still unknown. For this reason, we studied DOCA-salt treated Sprague-Dawley rats at weeks 2, 4, 6 and 12 and correlated the evolution of these profiles with cardiac hypertrophy and hypertension. Cardiac hypertrophy had a positive correlation with ANP expression in the left ventricle and with ANP plasma levels. BNP expression increased after 4 weeks of treatment while ANP increased significantly after 6 weeks. In addition, BNP plasma levels increased only in the group treated for 12 weeks, while ANP plasma levels increased from week 2. NP secretion has a differential response in the early stages of the development of cardiac hypertrophy induced by the DOCA-salt model, with an early increase in ANP. As ANP levels were exceeded to those of BNP in all the DOCA-salt groups, ANP might be considered a more specific marker of volume overload.

Urodilatin increases renal dopamine uptake: intracellular network involved.

Dopamine and urodilatin promote natriuresis and diuresis through a common pathway that involves reversible deactivation of renal Na+, K+-ATPase. We have reported that urodilatin enhances dopamine uptake in outer renal cortex through the natriuretic peptide type A receptor. Moreover, urodilatin enhances dopamine-induced inhibition of Na+, K+-ATPase activity. The objective of the present work was to investigate the intracellular signals involved in urodilatin effects on dopamine uptake in renal cortex of kidney rats. We show that urodilatin-elicited increase in ³H-dopamine was blunted by methylene blue (10 µM), a non-specific guanylate cyclase inhibitor, and by phorbol-12-myristate-13-acetate (1 µM), a particulate guanylate cyclase inhibitor, but not by 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (10 µM), a specific soluble guanylate cyclase inhibitor; therefore the involvement of particulate guanylate cyclase on urodilatin mediated dopamine uptake was confirmed. Cyclic guanosine monophosphate and proteinkinase G were also implicated in the signaling pathway, since urodilatin effects were mimicked by the analog 125 µM 8-Br-cGMP and blocked by the proteinkinase G-specific inhibitor, KT-5823 (1 µM). In conclusion, urodilatin increases dopamine uptake in renal cortex stimulating natriuretic peptide type A receptor, which signals through particulate guanylate cyclase activation, cyclic guanosine monophosphate generation, and proteinkinase G activation. Dopamine and urodilatin may achieve their effects through a common pathway that involves deactivation of renal Na+, K+-ATPase, reinforcing their natriuretic and diuretic properties.