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SIGNIFICANCE STATEMENT: The effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on regional tubular sodium handling is poorly understood in humans. In this study, empagliflozin substantially decreased lithium reabsorption in the proximal tubule (PT) (a marker of proximal tubular sodium reabsorption), a magnitude out of proportion to that expected with only inhibition of sodium-glucose cotransporter-2. This finding was not driven by an "osmotic diuretic" effect; however, several parameters changed in a manner consistent with inhibition of the sodium-hydrogen exchanger 3. The large changes in proximal tubular handling were acutely buffered by increased reabsorption in both the loop of Henle and the distal nephron, resulting in the observed modest acute natriuresis with these agents. After 14 days of empagliflozin, natriuresis waned due to increased reabsorption in the PT and/or loop of Henle. These findings confirm in humans that SGLT2i have complex and important effects on renal tubular solute handling. BACKGROUND: The effect of SGLT2i on regional tubular sodium handling is poorly understood in humans but may be important for the cardiorenal benefits. METHODS: This study used a previously reported randomized, placebo-controlled crossover study of empagliflozin 10 mg daily in patients with diabetes and heart failure. Sodium handling in the PT, loop of Henle (loop), and distal nephron was assessed at baseline and day 14 using fractional excretion of lithium (FELi), capturing PT/loop sodium reabsorption. Assessments were made with and without antagonism of sodium reabsorption through the loop using bumetanide. RESULTS: Empagliflozin resulted in a large decrease in sodium reabsorption in the PT (increase in FELi=7.5%±10.6%, P = 0.001), with several observations suggesting inhibition of PT sodium hydrogen exchanger 3. In the absence of renal compensation, this would be expected to result in approximately 40 g of sodium excretion/24 hours with normal kidney function. However, rapid tubular compensation occurred with increased sodium reabsorption both in the loop ( P < 0.001) and distal nephron ( P < 0.001). Inhibition of sodium-glucose cotransporter-2 did not attenuate over 14 days of empagliflozin ( P = 0.14). However, there were significant reductions in FELi ( P = 0.009), fractional excretion of sodium ( P = 0.004), and absolute fractional distal sodium reabsorption ( P = 0.036), indicating that chronic adaptation to SGLT2i results primarily from increased reabsorption in the loop and/or PT. CONCLUSIONS: Empagliflozin caused substantial redistribution of intrarenal sodium delivery and reabsorption, providing mechanistic substrate to explain some of the benefits of this class. Importantly, the large increase in sodium exit from the PT was balanced by distal compensation, consistent with SGLT2i excellent safety profile. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov ( NCT03027960 ).
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Compuestos de Bencidrilo , Glucósidos , Insuficiencia Cardíaca , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Sodio , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Litio , Estudios Cruzados , Nefronas , Insuficiencia Cardíaca/tratamiento farmacológico , Diuréticos , GlucosaRESUMEN
BACKGROUND: Torsemide is proposed to have clinically important pharmacokinetic and pharmacodynamic advantages over furosemide. However, clinical outcomes did not differ in the Torsemide Comparison with Furosemide for Management of Heart Failure (TRANSFORM-HF) randomized trial. METHODS: We conducted a multicenter mechanistic substudy of patients with heart failure randomized to oral furosemide or torsemide (TRANSFORM-Mechanism). At baseline and 30 days, participants underwent detailed assessments of pharmacokinetic and pharmacodynamic parameters. RESULTS: TRANSFORM-Mechanism enrolled 88 participants. Kidney bioavailability, or the proportion of dose delivered to the tubular site of action, was significantly less with torsemide compared to furosemide [median 17.1%, (IQR 12.3, 23.5%) vs. 24.8% (16.6, 34.1%), p < 0.001]. Furosemide had a longer duration of kidney drug delivery and duration of natriuresis (p≤0.004 for both). Prescribed doses of furosemide and torsemide in TRANSFORM-Mechanism were similar to TRANSFORM-HF, with providers on average using a 2:1 dose equivalence conversion between drugs. However, these doses resulted in a substantially greater natriuresis with torsemide (p<0.001). A dose equivalence of â¼4:1 resulted in similar natriuresis. Higher diuretic doses in the torsemide group resulted in mild perturbations in kidney function and significant increases in renin, aldosterone, and norepinephrine (p<0.05 for all). Plasma volume (p=0.52) and body weight (p=0.89) did not improve with torsemide vs. furosemide. CONCLUSIONS: We observed no meaningful pharmacokinetic/pharmacodynamic advantages for torsemide vs. furosemide. The greater natriuresis from higher diuretic doses in the torsemide group was offset by greater neurohormonal activation and kidney dysfunction.
RESUMEN
BACKGROUND: People with the human immunodeficiency virus (PWH) have microvascular disease. Because perivascular adipose tissue (PVAT) regulates microvascular function and adipose tissue is inflamed in PWH, we tested the hypothesis that PWH have inflamed PVAT that impairs the function of their small vessels. METHODS: Subcutaneous small arteries were dissected with or without PVAT from a gluteal skin biopsy from 11 women with treated HIV (WWH) aged < 50 years and 10 matched women without HIV, and studied on isometric myographs. Nitric oxide (NO) and reactive oxygen species (ROS) were measured by fluorescence microscopy. Adipokines and markers of inflammation and ROS were assayed in PVAT. RESULTS: PVAT surrounding the small arteries in control women significantly (P < .05) enhanced acetylcholine-induced endothelium-dependent relaxation and NO, and reduced contractions to thromboxane and endothelin-1. However, these effects of PVAT were reduced significantly (P < .05) in WWH whose PVAT released less adiponectin but more markers of ROS and inflammation. Moderation of contractions by PVAT were correlated positively with adipose adiponectin. CONCLUSIONS: PVAT from WWH has oxidative stress, inflammation, and reduced release of adiponectin, which may contribute to enhanced contractions and therefore could promote small-artery dysfunction.
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Tejido Adiposo , Infecciones por VIH , Inflamación , Especies Reactivas de Oxígeno , Humanos , Femenino , Infecciones por VIH/fisiopatología , Infecciones por VIH/complicaciones , Tejido Adiposo/metabolismo , Adulto , Persona de Mediana Edad , Inflamación/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Estrés Oxidativo , Adiponectina/metabolismo , Óxido Nítrico/metabolismo , Arterias/fisiopatología , Arterias/patologíaRESUMEN
SGLT2 (sodium-glucose cotransporter 2) inhibitors interfere with the reabsorption of glucose and sodium in the early proximal renal tubule, but the magnitude and duration of any ensuing natriuretic or diuretic effect are the result of an interplay between the degree of upregulation of SGLT2 and sodium-hydrogen exchanger 3, the extent to which downstream compensatory tubular mechanisms are activated, and (potentially) the volume set point in individual patients. A comprehensive review and synthesis of available studies reveals several renal response patterns with substantial variation across studies and clinical settings. However, the common observation is an absence of a large acute or chronic diuresis or natriuresis with these agents, either when given alone or combined with other diuretics. This limited response results from the fact that renal compensation to these drugs is rapid and nearly complete within a few days or weeks, preventing progressive volume losses. Nevertheless, the finding that fractional excretion of glucose and lithium (the latter being a marker of proximal sodium reabsorption) persists during long-term treatment with SGLT2 inhibitors indicates that pharmacological tolerance to the effects of these drugs at the level of the proximal tubule does not meaningfully occur. This persistent proximal tubular effect of SGLT2 inhibitors can be hypothesized to produce a durable improvement in the internal set point for volume homeostasis, which may become clinically important during times of fluid expansion. However, it is difficult to know whether a treatment-related change in the volume set point actually occurs or contributes to the effect of these drugs to reduce the risk of major heart failure events. SGLT2 inhibitors exert cardioprotective effects by a direct effect on cardiomyocytes that is independent of the presence of or binding to SGLT2 or the actions of these drugs on the proximal renal tubule. Nevertheless, changes in the volume set point mediated by SGLT2 inhibitors might potentially act cooperatively with the direct favorable molecular and cellular effects of these drugs on cardiomyocytes to mediate their benefits on the development and clinical course of heart failure.
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Insuficiencia Cardíaca , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Cloruros , Transportador 2 de Sodio-Glucosa , Sodio , Agua , Homeostasis , Diuréticos , GlucosaRESUMEN
BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure or death from cardiovascular causes among patients with stable heart failure. However, the safety and efficacy of SGLT2 inhibitors when initiated soon after an episode of decompensated heart failure are unknown. METHODS: We performed a multicenter, double-blind trial in which patients with type 2 diabetes mellitus who were recently hospitalized for worsening heart failure were randomly assigned to receive sotagliflozin or placebo. The primary end point was the total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure (first and subsequent events). The trial ended early because of loss of funding from the sponsor. RESULTS: A total of 1222 patients underwent randomization (608 to the sotagliflozin group and 614 to the placebo group) and were followed for a median of 9.0 months; the first dose of sotagliflozin or placebo was administered before discharge in 48.8% and a median of 2 days after discharge in 51.2%. Among these patients, 600 primary end-point events occurred (245 in the sotagliflozin group and 355 in the placebo group). The rate (the number of events per 100 patient-years) of primary end-point events was lower in the sotagliflozin group than in the placebo group (51.0 vs. 76.3; hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.85; P<0.001). The rate of death from cardiovascular causes was 10.6 in the sotagliflozin group and 12.5 in the placebo group (hazard ratio, 0.84; 95% CI, 0.58 to 1.22); the rate of death from any cause was 13.5 in the sotagliflozin group and 16.3 in the placebo group (hazard ratio, 0.82; 95% CI, 0.59 to 1.14). Diarrhea was more common with sotagliflozin than with placebo (6.1% vs. 3.4%), as was severe hypoglycemia (1.5% vs. 0.3%). The percentage of patients with hypotension was similar in the sotagliflozin group and the placebo group (6.0% and 4.6%, respectively), as was the percentage with acute kidney injury (4.1% and 4.4%, respectively). The benefits of sotagliflozin were consistent in the prespecified subgroups of patients stratified according to the timing of the first dose. CONCLUSIONS: In patients with diabetes and recent worsening heart failure, sotagliflozin therapy, initiated before or shortly after discharge, resulted in a significantly lower total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure than placebo. (Funded by Sanofi and Lexicon Pharmaceuticals; SOLOIST-WHF ClinicalTrials.gov number, NCT03521934.).
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glicósidos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Lesión Renal Aguda/inducido químicamente , Anciano , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/mortalidad , Diabetes Mellitus Tipo 2/complicaciones , Método Doble Ciego , Femenino , Glicósidos/efectos adversos , Insuficiencia Cardíaca/complicaciones , Hospitalización/estadística & datos numéricos , Humanos , Hipotensión/inducido químicamente , Masculino , Persona de Mediana Edad , Transportador 1 de Sodio-Glucosa/antagonistas & inhibidores , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversosRESUMEN
Dr Irvine Page proposed the Mosaic Theory of Hypertension in the 1940s advocating that hypertension is the result of many factors that interact to raise blood pressure and cause end-organ damage. Over the years, Dr Page modified his paradigm, and new concepts regarding oxidative stress, inflammation, genetics, sodium homeostasis, and the microbiome have arisen that allow further refinements of the Mosaic Theory. A constant feature of this approach to understanding hypertension is that the various nodes are interdependent and that these almost certainly vary between experimental models and between individuals with hypertension. This review discusses these new concepts and provides an introduction to other reviews in this compendium of Circulation Research.
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Hipertensión/fisiopatología , Aldosterona/fisiología , Angiotensina II/farmacología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Vasos Sanguíneos/fisiología , Líquidos Corporales/fisiología , Sistema Nervioso Central/fisiología , Humanos , Hipertensión/etiología , Inflamación/complicaciones , Riñón/fisiología , Microbiota/fisiología , Especies Reactivas de Oxígeno/metabolismo , Factores de Riesgo , Cloruro de Sodio/administración & dosificación , Cloruro de Sodio/efectos adversos , Vasoconstrictores/farmacologíaRESUMEN
Intrarenal autoregulatory mechanisms maintain renal blood flow (RBF) and glomerular filtration rate (GFR) independent of renal perfusion pressure (RPP) over a defined range (80-180 mmHg). Such autoregulation is mediated largely by the myogenic and the macula densa-tubuloglomerular feedback (MD-TGF) responses that regulate preglomerular vasomotor tone primarily of the afferent arteriole. Differences in response times allow separation of these mechanisms in the time and frequency domains. Mechanotransduction initiating the myogenic response requires a sensing mechanism activated by stretch of vascular smooth muscle cells (VSMCs) and coupled to intracellular signaling pathways eliciting plasma membrane depolarization and a rise in cytosolic free calcium concentration ([Ca(2+)]i). Proposed mechanosensors include epithelial sodium channels (ENaC), integrins, and/or transient receptor potential (TRP) channels. Increased [Ca(2+)]i occurs predominantly by Ca(2+) influx through L-type voltage-operated Ca(2+) channels (VOCC). Increased [Ca(2+)]i activates inositol trisphosphate receptors (IP3R) and ryanodine receptors (RyR) to mobilize Ca(2+) from sarcoplasmic reticular stores. Myogenic vasoconstriction is sustained by increased Ca(2+) sensitivity, mediated by protein kinase C and Rho/Rho-kinase that favors a positive balance between myosin light-chain kinase and phosphatase. Increased RPP activates MD-TGF by transducing a signal of epithelial MD salt reabsorption to adjust afferent arteriolar vasoconstriction. A combination of vascular and tubular mechanisms, novel to the kidney, provides for high autoregulatory efficiency that maintains RBF and GFR, stabilizes sodium excretion, and buffers transmission of RPP to sensitive glomerular capillaries, thereby protecting against hypertensive barotrauma. A unique aspect of the myogenic response in the renal vasculature is modulation of its strength and speed by the MD-TGF and by a connecting tubule glomerular feedback (CT-GF) mechanism. Reactive oxygen species and nitric oxide are modulators of myogenic and MD-TGF mechanisms. Attenuated renal autoregulation contributes to renal damage in many, but not all, models of renal, diabetic, and hypertensive diseases. This review provides a summary of our current knowledge regarding underlying mechanisms enabling renal autoregulation in health and disease and methods used for its study.
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Tasa de Filtración Glomerular , Riñón/irrigación sanguínea , Riñón/fisiopatología , Músculo Liso Vascular/fisiopatología , Circulación Renal , Animales , Canales de Calcio/metabolismo , Señalización del Calcio , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/fisiopatología , Homeostasis , Humanos , Hipertensión/metabolismo , Hipertensión/fisiopatología , Riñón/metabolismo , Mecanotransducción Celular , Músculo Liso Vascular/metabolismo , Arteria Renal/metabolismo , Arteria Renal/fisiopatología , VasoconstricciónRESUMEN
BACKGROUND: In the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) trial, sotagliflozin, a sodium-glucose cotransporter-1 and sodium-glucose cotransporter-2 inhibitor, reduced total occurrences of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure relative to placebo by 33%. OBJECTIVE: To determine whether sotagliflozin increased the prespecified efficacy outcome of days alive and out of the hospital (DAOH) in the SOLOIST-WHF trial. DESIGN: Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT03521934). SETTING: 306 sites in 32 countries. PARTICIPANTS: 1222 patients with type 2 diabetes and reduced or preserved ejection fraction who were recently hospitalized for worsening heart failure. INTERVENTION: 200 mg of sotagliflozin once daily (with a possible dose increase to 400 mg) or matching placebo. MEASUREMENTS: The primary analysis included hospitalizations for any reason on the basis of investigator-reported incidence and duration of admissions after randomization. Days alive and out of the hospital and its converse (days dead and days in the hospital) were analyzed using prespecified Poisson regression models. RESULTS: Although similar proportions of patients in the sotagliflozin and placebo groups were hospitalized at least once (38.5% vs. 41.4%), fewer patients in the sotagliflozin group were hospitalized more than once (16.3% vs. 22.1%). There were 64 and 76 deaths in the sotagliflozin and placebo groups, respectively. The DAOH rate in the sotagliflozin group was 3% higher than in the placebo group (rate ratio [RR], 1.03 [95% CI, 1.00 to 1.06]; P = 0.027). This difference was primarily driven by a reduction in the rate of days dead (RR, 0.71 [CI, 0.52 to 0.99]; P = 0.041) rather than by a reduction in the rate of days hospitalized for any cause. For every 100 days of follow-up, patients in the sotagliflozin group were alive and out of the hospital for 3% or 2.9 more days than those in the placebo group (91.8 vs. 88.9 days); this difference reflected a 2.6-day difference in days dead (6.3 vs. 8.9 days) and a 0.3-day difference in days in the hospital (1.9 vs. 2.2 days). LIMITATION: Other than heart failure, the primary reason for each hospitalization was unspecified. CONCLUSION: Sotagliflozin increased DAOH, a metric that may provide an additional patient-centered outcome to capture the totality of disease burden. Future studies are needed to quantify the consequences of increasing DAOH in terms of health economics and patient quality of life. PRIMARY FUNDING SOURCE: Sanofi at initiation and Lexicon Pharmaceuticals at completion.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glicósidos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Anciano , Diabetes Mellitus Tipo 2/mortalidad , Método Doble Ciego , Femenino , Insuficiencia Cardíaca/mortalidad , Hospitalización , Humanos , Masculino , Persona de Mediana EdadRESUMEN
AIMS: In healthy volunteers, the kidney deploys compensatory post-diuretic sodium reabsorption (CPDSR) following loop diuretic-induced natriuresis, minimizing sodium excretion and producing a neutral sodium balance. CPDSR is extrapolated to non-euvolemic populations as a diuretic resistance mechanism; however, its importance in acute decompensated heart failure (ADHF) is unknown. METHODS AND RESULTS: Patients with ADHF in the Mechanisms of Diuretic Resistance cohort receiving intravenous loop diuretics (462 administrations in 285 patients) underwent supervised urine collections entailing an immediate pre-diuretic spot urine sample, then 6-h (diuretic-induced natriuresis period) and 18-h (post-diuretic period) urine collections. The average spot urine sodium concentration immediately prior to diuretic administration [median 15 h (13-17) after last diuretic] was 64 ± 33 mmol/L with only 4% of patients having low (<20 mmol/L) urine sodium consistent with CPDSR. Paradoxically, greater 6-h diuretic-induced natriuresis was associated with larger 18-h post-diuretic spontaneous natriuresis (r = 0.7, P < 0.001). Higher pre-diuretic urine sodium to creatinine ratio (r = 0.37, P < 0.001) was the strongest predictor of post-diuretic spontaneous natriuresis. In a subgroup of patients (n = 43) randomized to protocol-driven intensified diuretic therapies, the mean diuretic-induced natriuresis increased three-fold. In contrast to the substantial decrease in spontaneous natriuresis predicted by CPDSR, no change in post-diuretic spontaneous natriuresis was observed (P = 0.47). CONCLUSION: On a population level, CPDSR was not an important driver of diuretic resistance in hypervolemic ADHF. Contrary to CPDSR, a greater diuretic-induced natriuresis predicted a larger post-diuretic spontaneous natriuresis. Basal sodium avidity, rather than diuretic-induced CPDSR, appears to be the predominant determinate of both diuretic-induced and post-diuretic natriuresis in hypervolemic ADHF.
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Insuficiencia Cardíaca , Sodio , Diuréticos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Natriuresis , Inhibidores del Simportador de Cloruro Sódico y Cloruro PotásicoRESUMEN
Congestion is the primary pathophysiological lesion in most heart failure (HF) hospitalizations. Renal congestion increases renal tubular pressure, reducing glomerular filtration rate (GFR) and diuresis. Because each nephron is a fluid-filled column, renal negative pressure therapy (rNPT) applied to the urinary collecting system should reduce tubular pressure, potentially improving kidney function. We evaluated the renal response to rNPT in congestive HF. Ten anesthetized â¼80-kg pigs underwent instrumentation with bilateral renal pelvic JuxtaFlow catheters. GFR was determined by iothalamate clearance (mGFR) and renal plasma flow (RPF) by para-aminohippurate clearance. Each animal served as its own control with randomization of left versus right kidney to -30 mmHg rNPT or no rNPT. mGFR and RPF were measured simultaneously from the rNPT and no rNPT kidney. Congestive HF was induced via cardiac tamponade maintaining central venous pressure at 20-22.5 mmHg throughout the experiment. Before HF induction, rNPT increased natriuresis, diuresis, and mGFR compared with the control kidney (P < 0.001 for all). Natriuresis, diuresis, and mGFR decreased following HF (P < 0.001 for all) but were higher in rNPT kidney versus control (P < 0.001 for all). RPF decreased during HF (P < 0.001) without significant differences between rNPT treatments. During HF, the rNPT kidney had similar diuresis and natriuresis (P > 0.5 for both) and higher fractional excretion of sodium (P = 0.001) compared with the non-rNPT kidney in the no HF period. In conclusion, rNPT resulted in significantly increased diuresis, natriuresis, and mGFR, with or without experimental HF. rNPT improved key renal parameters of the congested cardiorenal phenotype.
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Síndrome Cardiorrenal/terapia , Diuresis , Fluidoterapia , Tasa de Filtración Glomerular , Insuficiencia Cardíaca/terapia , Riñón/fisiopatología , Animales , Síndrome Cardiorrenal/diagnóstico , Síndrome Cardiorrenal/fisiopatología , Modelos Animales de Enfermedad , Diuresis/efectos de los fármacos , Femenino , Furosemida/administración & dosificación , Tasa de Filtración Glomerular/efectos de los fármacos , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Hemodinámica , Infusiones Intravenosas , Riñón/efectos de los fármacos , Natriuresis , Flujo Plasmático Renal , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/administración & dosificación , Sus scrofaRESUMEN
BACKGROUND: Hypertension commonly complicates CKD. Vascular smooth muscle cells (VSMCs) of resistance arteries receive signals from the sympathetic nervous system that induce an endothelial cell (EC)-dependent anticontractile response that moderates vasoconstriction. However, the specific role of this pathway in the enhanced vasoconstriction in CKD is unknown. METHODS: A mouse model of CKD hypertension generated with 5/6-nephrectomy (5/6Nx) was used to investigate the hypothesis that an impaired anticontractile mechanism enhances sympathetic vasoconstriction. In vivo, ex vivo (isolated mesenteric resistance arteries), and in vitro (VSMC and EC coculture) models demonstrated neurovascular transmission and its contribution to vascular resistance. RESULTS: By 4 weeks, 5/6Nx mice (versus sham) had augmented increases in mesenteric vascular resistance and mean arterial pressure with carotid artery occlusion, accompanied by decreased connexin 43 (Cx43) expression at myoendothelial junctions (MEJs), impaired gap junction function, decreased EC-dependent hyperpolarization (EDH), and enhanced contractions. Exposure of VSMCs to NE for 24 hours in a vascular cell coculture decreased MEJ Cx43 expression and MEJ gap junction function. These changes preceded vascular structural changes evident only at week 8. Inhibition of central sympathetic outflow or transfection of Cx43 normalized neurovascular transmission and vasoconstriction in 5/6Nx mice. CONCLUSIONS: 5/6Nx mice have enhanced neurovascular transmission and vasoconstriction from an impaired EDH anticontractile component before vascular structural changes. These neurovascular changes depend on an enhanced sympathetic discharge that impairs the expression of Cx43 in gap junctions at MEJs, thereby interrupting EDH responses that normally moderate vascular tone. Dysregulation of neurovascular transmission may contribute to the development of hypertension in CKD.
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Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Transmisión Sináptica/fisiología , Resistencia Vascular/fisiología , Vasoconstricción/fisiología , Animales , Técnicas de Cultivo de Célula , Conexina 43/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales , Uniones Comunicantes/metabolismo , Masculino , Arterias Mesentéricas/metabolismo , Arterias Mesentéricas/fisiopatología , Ratones , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Insuficiencia Renal Crónica/etiologíaRESUMEN
ABSTRACT: The high mortality of specific groups from COVID-19 highlights the importance of host-viral interactions and the potential benefits from enhancing host defenses. SARS-CoV-2 requires angiotensin-converting enzyme (ACE) 2 as a receptor for cell entry and infection. Although both ACE inhibitors and spironolactone can upregulate tissue ACE2, there are important points of discrimination between these approaches. The virus requires proteolytic processing of its spike protein by transmembrane protease receptor serine type 2 (TMPRSS2) to enable binding to cellular ACE2. Because TMPRSS2 contains an androgen promoter, it may be downregulated by the antiandrogenic actions of spironolactone. Furin and plasmin also process the spike protein. They are inhibited by protease nexin 1 or serpin E2 (PN1) that is upregulated by angiotensin II but downregulated by aldosterone. Therefore, spironolactone should selectively downregulate furin and plasmin. Furin also promotes pulmonary edema, whereas plasmin promotes hemovascular dysfunction. Thus, a downregulation of furin and plasmin by PN1 could be a further benefit of MRAs beyond their well-established organ protection. We review the evidence that spironolactone may be the preferred RASSi to increase PN1 and decrease TMPRSS2, furin, and plasmin activities and thereby reduce viral cell binding, entry, infectivity, and bad outcomes. This hypothesis requires direct investigation.
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Tratamiento Farmacológico de COVID-19 , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Sistema Renina-Angiotensina/efectos de los fármacos , Espironolactona/uso terapéutico , Humanos , Serina Endopeptidasas/efectos de los fármacosRESUMEN
INTRODUCTION: Furosemide reduces the glomerular filtration rate (GFR) and increases the renal vascular resistance (RVR) despite inhibiting tubuloglomerular feedback but increases proximal tubule pressure, renin release, and renal nerve activity. OBJECTIVE: This study tested the hypothesis that the fall in GFR with furosemide is due to volume depletion or activation of angiotensin type 1 (AT1) receptors or renal nerves. METHODS: Furosemide was infused for 60 min at 1.0 mg·kg-1·h-1 in groups of 5-8 anesthetized rats. Additional groups received intravenous volume replacement to prevent fluid and Na+ losses or volume replacement plus losartan or plus sham denervation or plus renal denervation or renal nerve deafferentation. RESULTS: At 60 min of infusion, furosemide alone reduced the GFR (-37 ± 4%; p < 0.01). This fall was not prevented by volume replacement or pretreatment with losartan, although losartan moderated the increase in RVR with furosemide (+44 ± 3 vs. +82 ± 7%; p < 0.01). Whereas the GFR fell after furosemide in rats after sham procedure (-31 ± 2%), it was not changed significantly after prior renal deafferentation. Proximal tubule pressure increased significantly but returned towards baseline over 60 min of furosemide, while urine output remained elevated, and GFR and renal blood flow depressed. CONCLUSIONS: The fall in GFR over 60 min of furosemide infusion is independent of volume depletion or activation of AT1 receptors but is largely dependent on renal afferent nerves.
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Furosemida/uso terapéutico , Tasa de Filtración Glomerular/efectos de los fármacos , Infusiones Intravenosas/métodos , Riñón/inervación , Animales , Modelos Animales de Enfermedad , Furosemida/farmacología , Humanos , RatasRESUMEN
Although cardiovascular disease is a major health burden for patients with chronic kidney disease, most cardiovascular outcome trials have excluded patients with advanced chronic kidney disease. Moreover, the major cardiovascular outcome trials that have been conducted in patients with end-stage renal disease have not demonstrated a treatment benefit. Thus, clinicians have limited evidence to guide the management of cardiovascular disease in patients with chronic kidney disease, particularly those on dialysis. Several factors contribute to both the paucity of trials and the apparent lack of observed treatment effect in completed studies. Challenges associated with conducting trials in this population include patient heterogeneity, complexity of renal pathophysiology and its interaction with cardiovascular disease, and competing risks for death. The Investigator Network Initiative Cardiovascular and Renal Clinical Trialists (INI-CRCT), an international organization of academic cardiovascular and renal clinical trialists, held a meeting of regulators and experts in nephrology, cardiology, and clinical trial methodology. The group identified several research priorities, summarized in this paper, that should be pursued to advance the field towards achieving improved cardiovascular outcomes for these patients. Cardiovascular and renal clinical trialists must partner to address the uncertainties in the field through collaborative research and design clinical trials that reflect the specific needs of the chronic and end-stage kidney disease populations, with the shared goal of generating robust evidence to guide the management of cardiovascular disease in patients with kidney disease.
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Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/terapia , Fallo Renal Crónico/terapia , Insuficiencia Renal Crónica/complicaciones , Enfermedades Cardiovasculares/epidemiología , Sistema Cardiovascular/fisiopatología , Ensayos Clínicos como Asunto , Creatinina/sangre , Humanos , Prácticas Interdisciplinarias/métodos , Riñón/fisiopatología , Manejo de Atención al Paciente/métodos , Selección de Paciente , Diálisis Renal/métodos , Insuficiencia Renal Crónica/epidemiología , Proyectos de Investigación/tendenciasRESUMEN
BACKGROUND: Residual kidney function (RKF) conveys a survival benefit among dialysis patients, but the mechanism remains unclear. Improved volume control, clearance of protein-bound and middle molecules, reduced inflammation and preserved erythropoietin and vitamin D production are among the proposed mechanisms. Preservation of RKF requires techniques to measure it accurately to be able to uncover factors that accelerate its loss and interventions that preserve it and ultimately to individualize therapy. The average of renal creatinine and urea clearance provides a superior estimate of RKF in dialysis patients, when compared with daily urine volume. However, both involve the difficult task of obtaining an accurate 24-h urine sample. SUMMARY: In this article, we first review the definition and measurement of RKF, including newly proposed markers such as serum levels of beta2-microglobulin, cystatin C and beta-trace protein. We then discuss the predictors of RKF loss in new dialysis patients. We review several strategies to preserve RKF such as renin-angiotensin-aldosterone system blockade, incremental dialysis, use of biocompatible membranes and ultrapure dialysate in hemodialysis (HD) patients, and use of biocompatible solutions in peritoneal dialysis (PD) patients. Despite their generally adverse effects on renal function, aminoglycoside antibiotics have not been shown to have adverse effects on RKF in well-hydrated patients with end-stage renal disease (ESRD). Presently, the roles of better blood pressure control, diuretic usage, diet, and dialysis modality on RKF remain to be clearly established. Key Messages: RKF is an important and favorable prognostic indicator of reduced morbidity, mortality, and higher quality of life in both PD an HD patients. Further investigation is warranted to uncover factors that protect or impair RKF. This should lead to improved quality of life and prolonged lifespan in patients with ESRD and cost-reduction through patient centeredness, individualized therapy, and precision medicine approaches.
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Fallo Renal Crónico/terapia , Pruebas de Función Renal , Riñón/fisiopatología , Diálisis Renal/métodos , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Soluciones para Diálisis , Tasa de Filtración Glomerular/fisiología , Humanos , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/mortalidad , Fallo Renal Crónico/fisiopatología , Calidad de Vida , Diálisis Renal/instrumentación , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Resultado del TratamientoRESUMEN
The underlying mechanism by which amassing of white adipose tissue in obesity regulates sympathetic nerve system (SNS) drive to the tissues responsible for glucose disposal, and causes insulin resistance (IR), remains unknown. We tested the hypothesis that high-fat (HF) feeding increases afferent impulses from white adipose tissue that reflexively elevate efferent nerve activity to skeletal muscle (SM) and adipose tissue to impair their local glucose uptake. We also investigated how salt-intake can enhance IR. HF-fed rats received a normal salt (0.4%) or high salt (4%) diet for 3 weeks. High-salt intake in HF fed rats decreased insulin-stimulated 2-deoxyglucose uptake by over 30% in white adipose tissue and SM, exacerbated inflammation, and impaired their insulin signaling and glucose transporter 4 (Glut4) trafficking. Dietary salt in HF fed rats also increased the activity of the adipose-cerebral-muscle renin-angiotensin system (RAS) axes, SNS, and reactive oxygen species (ROS). Insulin sensitivity was reduced by 32% in HF rats during high-salt intake, but was improved by over 62% by interruption of central RAS and SNS drive, and by over 45% by denervation or deafferentation of epididymal fat (all P<0.05). Our study suggest that a HF diet engages a sympathetic reflex from the white adipose tissue that activates adipose-cerebral-muscle RAS/ROS axes and coordinates a reduction in peripheral glucose uptake. These are all enhanced by salt-loading. These findings provide new insight into the role of a reflex initiated in adipose tissue in the regulation of glucose homeostasis during HF feeding that could lead to new therapeutic approaches to IR.
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Tejido Adiposo/metabolismo , Encéfalo/metabolismo , Dieta Alta en Grasa/efectos adversos , Resistencia a la Insulina , Sistema Nervioso Simpático/metabolismo , Adipocitos , Tejido Adiposo/fisiología , Animales , Encéfalo/fisiología , Transportador de Glucosa de Tipo 4/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Sistema Renina-Angiotensina , Sodio en la Dieta/administración & dosificación , Sodio en la Dieta/efectos adversos , Sistema Nervioso Simpático/fisiologíaRESUMEN
Nitric oxide prevents hypertension yet enhances proximal tubule Na+ reabsorption. Nitric oxide synthase is inhibited by asymmetric dimethylarginine (ADMA) that is metabolized by dimethylarginine dimethylaminohydrolase (DDAH) whose type 1 isoform is expressed abundantly in the proximal tubule (PT). We hypothesize that ADMA metabolized by DDAH-1 inhibits fluid reabsorbtion (Jv) by the proximal tubule. S2 segments of the PT were microperfused between blocks in vivo to assess Jv in anesthetized rats. Compared with vehicle, microperfusion of ADMA or Nω-nitro-l-arginine methyl ester (l-NAME) in the proximal tubule reduced Jv dose dependently. At 10-4 mol/l both reduced Jv by ~40% (vehicle: 3.2 ± 0.7 vs. ADMA: 2.1 ± 0.5, P < 0.01 vs. l-NAME: 1.9 ± 0.4 nl·min-1·mm-1, P < 0.01; n = 10). Selective inhibition of DDAH-1 in rats with intravenous L-257 (60 mg/kg) given 2 h before and L-257 (10-5 mol/l) perfused in the proximal tubule for 5 min reduced Jv by 32 ± 4% (vehicle: 3.2 ± 0.5 vs. L-257: 2.2 ± 0.5 nl·min-1·mm-1; P < 0.01) and increased plasma ADMA by ≈50% (vehicle: 0.46 ± 0.03 vs. L-257: 0.67 ± 0.03 µmol/l, P < 0.0001) without changing plasma symmetric dimethylarginine. Compared with nontargeted control small-interference RNA, knock down of DDAH-1 in mice by 60% with targeted small-interference RNAs (siRNA) reduced Jv by 29 ± 5% (nontargeted siRNA: 2.8 ± 0.20 vs. DDAH-1 knockdown: 1.9 ± 0.31 nl·min-1·mm-1, P < 0.05). In conclusion, fluid reabsorption in the proximal tubule is reduced by tubular ADMA or by blocking its metabolism by DDAH-1. L-257 is a novel regulator of proximal tubule fluid reabsorption.
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Amidohidrolasas/metabolismo , Arginina/análogos & derivados , Túbulos Renales Proximales/enzimología , Reabsorción Renal , Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/genética , Animales , Arginina/metabolismo , Arginina/farmacología , Inhibidores Enzimáticos/farmacología , Túbulos Renales Proximales/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Óxido Nítrico/metabolismo , Interferencia de ARN , Ratas Sprague-Dawley , Reabsorción Renal/efectos de los fármacosRESUMEN
Nuclear factor erythyroid factor 2 (Nrf2) transcribes genes in cultured endothelial cells that reduce reactive oxygen species (ROS) and generate nitric oxide (NO) or metabolize asymmetric dimethylarginine (ADMA), which inhibits NO synthase (NOS). Therefore, we undertook a functional study to test the hypothesis that activation of Nrf2 by tert-butylhydroquinone (tBHQ) preserves microvascular endothelial function during oxidative stress. Wild-type CB57BL/6 (wt), Nrf2 wt (+/+), or knockout (-/-) mice received vehicle (Veh) or tBHQ (0.1%; activator of Nrf2) during 14-day infusions of ANG II (to induce oxidative stress) or sham. MAP was recorded by telemetry. Mesenteric resistance arterioles were studied on isometric myographs and vascular NO and ROS by fluorescence microscopy. ANG II increased the mean arterial pressure (112 ± 5 vs. 145 ± 5 mmHg; P < 0.01) and excretion of 8-isoprostane F2α (2.8 ± 0.3 vs. 3.8 ± 0.3 ng/mg creatinine; P < 0.05) at 12-14 days. However, 12 days of ANG II reduced endothelium-derived relaxation (27 ± 5 vs. 17 ± 3%; P < 0.01) and NO (0.38 ± 0.07 vs. 0.18 ± 0.03 units; P < 0.01) but increased microvascular remodeling, endothelium-derived contractions (7.5 ± 0.5 vs. 13.0 ± 1.7%; P < 0.01), superoxide (0.09 ± 0.03 vs. 0.29 ± 0.08 units; P < 0.05), and contractions to U-46,619 (87 ± 6 vs. 118 ± 3%; P < 0.05), and endothelin-1(89 ± 4 vs. 123 ± 12%; P < 0.05). tBHQ prevented all of these effects of ANG II at 12-14 days in Nrf2+/+ mice but not in Nrf2-/- mice. In conclusion, tBHQ activates Nrf2 to prevent microvascular endothelial dysfunction, remodeling, and contractility, and moderate ADMA and hypertension at 12-14 days of ANG II infusion, thereby preserving endothelial function and preventing hypertension.
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Angiotensina II , Antihipertensivos/farmacología , Arginina/análogos & derivados , Presión Arterial/efectos de los fármacos , Hidroquinonas/farmacología , Hipertensión/prevención & control , Microvasos/efectos de los fármacos , Factor 2 Relacionado con NF-E2/agonistas , Estrés Oxidativo/efectos de los fármacos , Animales , Arginina/sangre , Biomarcadores/sangre , Modelos Animales de Enfermedad , Factores Relajantes Endotelio-Dependientes/metabolismo , Hipertensión/inducido químicamente , Hipertensión/metabolismo , Hipertensión/fisiopatología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Microvasos/metabolismo , Microvasos/fisiopatología , Factor 2 Relacionado con NF-E2/deficiencia , Factor 2 Relacionado con NF-E2/genética , Óxido Nítrico/metabolismo , Transducción de Señal/efectos de los fármacos , Tromboxano B2/metabolismo , Factores de Tiempo , Regulación hacia Arriba , Remodelación Vascular/efectos de los fármacos , Vasoconstricción/efectos de los fármacosRESUMEN
BACKGROUND/AIMS: Canonical Wnt signaling is involved in oxidative stress, vasculopathy and diabetes mellitus but its role in diabetic renal microvascular dysfunction is unclear. We tested the hypothesis that enhanced canonical Wnt signaling in renal afferent arterioles from diabetic mice increases reactive oxygen species (ROS) and contractions to endothelin-1 (ET-1). METHODS: Streptozotocin-induced diabetes or control C57Bl/6 mice received vehicle or sulindac (40 mg·kg-1·day-1) to block Wnt signaling for 4 weeks. ET-1 contractions were measured by changes of afferent arteriolar diameter. Arteriolar H2O2, O2 -, protein expression and enzymatic activity were assessed using sensitive fluorescence probes, immunoblotting and colorimetric assay separately. RESULTS: Compared to control, diabetic mouse afferent arteriole had increased O2- (+ 84%) and H2O2 (+ 91%) and enhanced responses to ET-1 at 10-8 mol·l-1 (-72±4% of versus -43±4%, P< 0.05) accompanied by reduced protein expressions and activities for catalase and superoxide dismutase 2 (SOD2). Arteriolar O2 - was increased further by ET-1 and contractions to ET-1 reduced by PEG-SOD in both groups whereas H2O2 unchanged by ET-1 and contractions were reduced by PEG-catalase selectively in diabetic mice. The Wnt signaling protein ß-catenin was upregulated (3.3-fold decrease in p-ß-catenin/ß-catenin) while the glycogen synthase kinase-3ß (GSK-3ß) was downregulated (2.6-fold increase in p-GSK-3ß/ GSK-3ß) in preglomerular vessels of diabetic mice. Sulindac normalized the Wnt signaling proteins, arteriolar O2 -, H2O2 and ET-1 contractions while doubling microvascular catalase and SOD2 expression in diabetic mice. CONCLUSION: Increased ROS, notably H2O2 contributes to enhanced afferent arteriolar responses to ET-1 in diabetes, which is closely associated with Wnt signaling. Antioxidant pharmacological strategies targeting Wnt signaling may improve vascular function in diabetic nephropathy.
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Arteriolas/efectos de los fármacos , Diabetes Mellitus Experimental/metabolismo , Endotelina-1/farmacología , Especies Reactivas de Oxígeno/metabolismo , Vasoconstricción/efectos de los fármacos , Vía de Señalización Wnt , Animales , Arteriolas/metabolismo , Peróxido de Hidrógeno , Riñón/irrigación sanguínea , RatonesRESUMEN
The Na+-K+-2Cl- cotransporter (NKCC2) on the loop of Henle is the site of action of furosemide. Because outer medullary potassium channel (ROMK) inhibitors prevent reabsorption by NKCC2, we tested the hypothesis that ROMK inhibition with a novel selective ROMK inhibitor (compound C) blocks tubuloglomerular feedback (TGF) and reduces vascular resistance. Loop perfusion of either ROMK inhibitor or furosemide caused dose-dependent blunting of TGF, but the response to furosemide was 10-fold more sensitive (IC50 = 10-6 M for furosemide and IC50 = 10-5 M for compound C). During systemic infusion, both diuretics inhibited TGF, but ROMK inhibitor was 10-fold more sensitive (compound C: 63% inhibition; furosemide: 32% inhibition). Despite blockade of TGF, 1 h of constant systemic infusion of both diuretics reduced the glomerular filtration rate (GFR) and renal blood flow (RBF) by 40-60% and increased renal vascular resistance (RVR) by 100-200%. Neither diuretic altered blood pressure or hematocrit. Proximal tubule hydrostatic pressures (PPT) increased transiently with both diuretics (compound C: 56% increase; furosemide: 70% increase) but returned to baseline. ROMK inhibitor caused more natriuresis (3,400 vs. 1,600% increase) and calciuresis (1,200 vs. 800% increase) but less kaliuresis (33 vs. 167% increase) than furosemide. In conclusion, blockade of ROMK or Na+-K+-2Cl- transport inhibits TGF yet increases renal vascular resistance. The renal vasoconstriction was independent of volume depletion, blood pressure, TGF, or PPT.