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The utility of Rituximab (RTX) for IgA vasculitis nephritis (IgAVN) is not well established. Up to now, we analysed the largest samples of IgAVN patients treated by RTX with a total of 41 retrieved subjects up to December 29, 2023 in the present systematic review. We assessed the clinical profiles, efficacy, and safety of RTX treatments. The present review showed that the renal function tended to be stabilized (P = 1.000) and urinalysis tended to normalize after RTX treatment with no serious adverse events reported. Moreover, 40% (16/40) of patients was freed use of glucocorticoid after RTX administration (P < 0.001). The remission rate was 92.7% (38/41) and complete remission rate was 46.3% (19/41) in IgAVN patients. Interestingly, 76.9% (10/13) of IgAVN child patients achieved complete remission when compared with 32.1% (9/28) of adult patients (P = 0.017). In summary, our results support the benefit of RTX therapy in IgAVN patients, especially children subjects.
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Rituximab , Humanos , Rituximab/uso terapéutico , Resultado del Tratamiento , Masculino , Adulto , Femenino , Factores Inmunológicos/uso terapéutico , Niño , Glomerulonefritis por IGA/tratamiento farmacológico , Inducción de Remisión , Vasculitis por IgA/tratamiento farmacológico , Nefritis/tratamiento farmacológico , Persona de Mediana Edad , Vasculitis/tratamiento farmacológicoRESUMEN
Hepatitis E Virus (HEV) infection is an emergent zoonotic disease of increasing concern in developed regions. HEV genotype 3 (HEV-3) is mainly transmitted through consumption of contaminated food in high-income countries and is classified into at least 13 subtypes (3a-3n), based on p-distance values from complete genomes. In Latin America, HEV epidemiology studies are very scant. Our group has previously detected HEV3 in clinical cases, swine, wild boars, captive white-collared peccaries, and spotted deer from Uruguay. Herein, we aimed to provide novel insights and an updated overview of the molecular epidemiology of zoonotic HEV in Uruguay, including data from wastewater-based surveillance studies. A thorough analysis of HEV whole genomes and partial ORF2 sequences from Uruguayan human and domestic pig strains showed that they formed a separate monophyletic cluster with high nucleotide identity and exhibited p-distance values over the established cut-off (0.093) compared with reference subtypes' sequences. Furthermore, we found an overall prevalence of 10.87% (10/92) in wastewater, where two samples revealed a close relationship with humans, and animal reservoirs/hosts isolates from Uruguay. In conclusion, a single, new HEV-3 subtype currently circulates in different epidemiological settings in Uruguay, and we propose its designation as 3o along with its reference sequence.
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Ciervos , Virus de la Hepatitis E , Hepatitis E , Enfermedades de los Porcinos , Porcinos , Animales , Humanos , Virus de la Hepatitis E/genética , Hepatitis E/epidemiología , Hepatitis E/veterinaria , Uruguay/epidemiología , Filogenia , Genotipo , Ciervos/genética , Sus scrofa/genética , Monitoreo del Ambiente , ARN Viral/genéticaRESUMEN
Introduction: Elevated plasma levels of extracellular vesicles have been associated with impaired placentation, angiogenesis imbalance, intravascular inflammation, and endothelial dysfunction in women with preeclampsia, thus suggesting that circulating vesicles may be a good therapeutic target for the treatment of the disease. Recently, statins have been considered a potential treatment for the prevention of preeclampsia because of their pleiotropic effects, including the improvement of endothelial dysfunction and inhibition of inflammatory responses. However, the effects of these drugs on circulating vesicles concentration in women at risk of preeclampsia have not been established. Herein, we aimed to assess the effects of pravastatin on circulating extracellular vesicle generation in women at high risk of term preeclampsia. Methods: In a sample of 68 singleton pregnant women participating in the multicenter, double-blind, placebo-controlled STATIN trial (Nº EducraCT 2016-005206-19 ISRCTN), 35 women received a placebo and 33 women received a 20 mg/day dose of pravastatin for approximately 3 weeks (from 35 to 37 weeks of gestation until delivery). Large extracellular vesicles were characterized and quantified by flow cytometry using annexin V and cell-specific antibodies directed against platelet, endothelial, leukocyte, and syncytiotrophoblast cell surface markers. Results: In women who received the placebo, a significant increase in the plasma levels of large extracellular vesicles from platelets (34%, p < 0.01), leukocytes (33%, p < 0.01), monocytes (60%, p < 0.01), endothelial cells (40%, p < 0.05), and syncytiotrophoblast cells (22%, p < 0.05) were observed. However, treatment with pravastatin significantly reduced the plasma levels of large extracellular vesicles from platelets (42%, p < 0.001), leukocytes (25%, p < 0.001), monocytes (61%, p < 0.001), endothelial cells (69%, p < 0.001), activated endothelial cells (55%, p < 0.001), and syncytiotrophoblast cells (44%, p < 0.001). Discussion: These results indicate that pravastatin reduces the levels of activated cell-derived membrane vesicles from the maternal vasculature, blood, and placental syncytiotrophoblast of women at high risk of term preeclampsia, suggesting that this statin may be beneficial in reducing endothelial dysfunction and pro-inflammatory and pro-coagulatory state characteristics of the disease.
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Anastomotic leakage (AL) is a defect of the intestinal wall at the anastomotic site and is one of the most severe complications in colorectal surgery. Previous studies have shown that the immune system response plays a significant role in the development of AL. In recent years, DAMPs (damage-associated molecular patterns) have been identified as cellular compounds with the ability to activate the immune system. The NLRP3 inflammasome plays an important role in the inflammatory responses which are mediated by DAMPs such as ATP, HSP proteins or uric acid crystals, when found in extracellular environments. Recent publications suggest that systemic concentration of DAMPs in patients with colorectal surgery may determine the inflammatory process and have a role in the occurrence of AL and other post-surgery complications. This review provides valuable knowledge about the current evidence supporting this hypothesis and highlights the possible role of these compounds in postoperative processes, which could open a new path to explore new strategies to prevent possible post-surgical complications.
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Anastomosis Quirúrgica , Fuga Anastomótica , Cirugía Colorrectal , Humanos , Alarminas , Anastomosis Quirúrgica/efectos adversos , Fuga Anastomótica/etiología , Complicaciones Posoperatorias/prevención & control , Periodo PosoperatorioRESUMEN
The nucleotide-binding domain leucine-rich repeat-receptor, pyrin domain-containing-3 (NLRP3) inflammasome contributes to the inflammatory response by activating caspase-1, which in turn participates in the maturation of interleukin (IL)-1ß and IL-18, which are mainly secreted via pyroptosis. Pyroptosis is a lytic type of cell death that is controlled by caspase-1 processing gasdermin D. The amino-terminal fragment of gasdermin D inserts into the plasma membrane, creating stable pores and enabling the release of several proinflammatory factors. The activation of NLRP3 inflammasome and pyroptosis has been involved in the progression of liver fibrosis and its end-stage cirrhosis, which is among the main etiologies for liver transplantation (LT). Moreover, the NLRP3 inflammasome is involved in ischemia-reperfusion injury and early inflammation and rejection after LT. In this review, we summarize the recent literature addressing the role of the NLRP3 inflammasome and pyroptosis in all stages involved in LT and argue the potential targeting of this pathway as a future therapeutic strategy to improve LT outcomes. Likewise, we also discuss the impact of graft quality influenced by donation after circulatory death and the expected role of machine perfusion technology to modify the injury response related to inflammasome activation.
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Inflamasomas , Trasplante de Hígado , Inflamasomas/metabolismo , Piroptosis , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Caspasa 1/metabolismoRESUMEN
Renal luminal sodium transport is essential for physiological blood pressure control, and abnormalities in this process are strongly implicated in the pathogenesis of essential hypertension. Renal G protein-coupled receptors (GPCRs) are critical for the regulation of the reabsorption of essential nutrients, ions, and water from the glomerular filtrate. Recently, we showed that GPCR 37L1 (GPR37L1) is expressed on the apical membrane of renal proximal tubules (RPT) and regulates luminal sodium transport and blood pressure by modulating the function of the sodium proton exchanger 3 (NHE3). However, little is known about GPR37L1 intracellular signaling. Here, we show that GPR37L1 is localized to the nuclear membrane, in addition to the plasma membrane in human RPT cells. Furthermore, GPR37L1 signals via the PI3K/AKT/mTOR pathway to decrease the expression of DNA (cytosine-5)-methyltransferase 1 (DNMT1) and enhance NHE3 transcription. Overall, we demonstrate the direct role of a nuclear membrane GPCR in the regulation of renal sodium through epigenetic gene regulation.
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Fosfatidilinositol 3-Quinasas , Intercambiadores de Sodio-Hidrógeno , Humanos , Intercambiador 3 de Sodio-Hidrógeno/genética , Intercambiador 3 de Sodio-Hidrógeno/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Intercambiadores de Sodio-Hidrógeno/genética , Intercambiadores de Sodio-Hidrógeno/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Sodio/metabolismo , Epigénesis GenéticaRESUMEN
Inflammasomes, particularly the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3 (NLRP3) inflammasome, apparently serve as crucial regulators of the inflammatory response through the activation of Caspase-1 and induction of pro-inflammatory cytokines and pyroptotic cell death. Pyroptosis is a type of programmed cell death mediated by Caspase-1 cleavage of Gasdermin D and the insertion of its N-terminal fragment into the plasma membrane, where it forms pores, enabling the release of different pro-inflammatory mediators. Pyroptosis is considered not only a pro-inflammatory pathway involved in liver pathophysiology but also an important pro-fibrotic mediator. Diverse molecular mechanisms linking oxidative stress, inflammasome activation, pyroptosis, and the progression of liver pathologies have been documented. Numerous studies have indicated the protective effects of several antioxidants, with the ability to induce nuclear factor erythroid 2-related factor 2 (Nrf2) activity on liver inflammation and fibrosis. In this review, we have summarised recent studies addressing the role of the NLRP3 inflammasome and pyroptosis in the pathogenesis of various hepatic diseases, highlighting the potential application of Nrf2 inducers in the prevention of pyroptosis as liver protective compounds.
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Gastrin, secreted by G-cells, and glucagon-like peptide-1 (GLP-1), secreted by L-cells, may participate in the regulation of sodium balance. We studied the effect of sodium in mice in vivo and mouse ileum and human L-cells, on GLP-1 secretion, and the role of NFAT5 and gastrin-releasing peptide receptor (GRPR) in this process. A high-sodium diet increases serum GLP-1 levels in mice. Increasing sodium concentration stimulates GLP-1 secretion from mouse ileum and L-cells. GRP enhances the high sodium-induced increase in GLP-1 secretion. High sodium increases cellular GLP-1 expression, while low and high sodium concentrations increase NFAT5 and GRPR expression. Silencing NFAT5 in L-cells abrogates the stimulatory effect of GRP on the high sodium-induced GLP-1 secretion and protein expression, and the sodium-induced increase in GRPR expression. GLP-1 and gastrin decrease the expression of Na+-K+/ATPase and increase the phosphorylation of sodium/hydrogen exchanger type 3 (NHE3) in human renal proximal tubule cells (hRPTCs). This study gives a new perspective on the mechanisms of GLP-1 secretion, especially that engendered by ingested sodium, and the ability of GLP-1, with gastrin, to decrease Na+-K+/ATPase expression and NHE3 function in hRPTCs. These results may contribute to the better utilization of current and future GLP-1-based drugs in the treatment of hypertension.
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Gastrinas/genética , Péptido 1 Similar al Glucagón/genética , Receptor del Péptido 1 Similar al Glucagón/genética , Hipertensión/genética , Factores de Transcripción/genética , Animales , Células Secretoras de Gastrina/metabolismo , Regulación de la Expresión Génica/genética , Silenciador del Gen , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/patología , Túbulos Renales Proximales/metabolismo , Ratones , Fosforilación/efectos de los fármacos , Sodio/metabolismo , Sodio/farmacología , Intercambiador 3 de Sodio-Hidrógeno/genética , ATPasa Intercambiadora de Sodio-Potasio/genéticaRESUMEN
Significance: Kidney diseases remain a worldwide public health problem resulting in millions of deaths each year; they are characterized by progressive destruction of renal function by sustained inflammation. Pyroptosis is a lytic type of programmed cell death involved in inflammation, as well as a key fibrotic mechanism that is critical in the development of kidney pathology. Pyroptosis is induced by the cleavage of Gasdermins by various caspases and is executed by the insertion of the N-terminal fragment of cleaved Gasdermins into the plasma membrane, creating oligomeric pores and allowing the release of diverse proinflammatory products into the extracellular space. Inflammasomes are multiprotein complexes leading to the activation of caspase-1, which will cleave Gasdermin D, releasing several proinflammatory cytokines; this results in the initiation and amplification of the inflammatory response. Recent Advances: The efficacy of Gasdermin D cleavage is reduced by a change in the redox balance. Recently, several studies have shown that the attenuation of reactive oxygen species (ROS) production induced by antioxidant pathways results in a reduction of renal pyroptosis. In this review, we discuss the role of pyroptosis in the pathogenesis of chronic kidney disease (CKD) and acute kidney disease; summarize the clinical outcomes and different molecular mechanisms leading to Gasdermin activation; and examine studies about the capacity of antioxidants, particularly Nrf2 activators, to ameliorate Gasdermin activity. Future Directions: We illustrate the potential influence of the deregulation of redox balance on inflammasome activity and pyroptosis as a novel therapeutic approach for the treatment of kidney diseases. Antioxid. Redox Signal. 35, 40-60.
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Lesión Renal Aguda/metabolismo , Citocinas/metabolismo , Riñón/metabolismo , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Piroptosis/fisiología , Insuficiencia Renal Crónica/metabolismo , Lesión Renal Aguda/patología , Alarminas/metabolismo , Animales , Caspasa 1/metabolismo , Espacio Extracelular , Fibrosis , Humanos , Inflamasomas/metabolismo , Riñón/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Mitocondrias/metabolismo , Oxidación-Reducción , Moléculas de Patrón Molecular Asociado a Patógenos/metabolismo , Proteínas de Unión a Fosfato/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Insuficiencia Renal Crónica/patologíaRESUMEN
Inflammasomes are components of the innate immune response that have recently emerged as crucial controllers of tissue homeostasis. In particular, the nucleotide-binding domain, leucine-rich-containing (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is a complex platform involved in the activation of caspase-1 and the maturation of interleukin (IL)-1ß and IL-18, which are mainly released via pyroptosis. Pyroptosis is a caspase-1-dependent type of cell death that is mediated by the cleavage of gasdermin D and the subsequent formation of structurally stable pores in the cell membrane. Through these pores formed by gasdermin proteins cytosolic contents are released into the extracellular space and act as damage-associated molecular patterns, which are pro-inflammatory signals. Inflammation is a main contributor to the development of hypertension and it also is known to stimulate fibrosis and end-organ damage. Patients with essential hypertension and animal models of hypertension exhibit elevated levels of circulating IL-1ß. Downregulation of the expression of key components of the NLRP3 inflammasome delays the development of hypertension and pharmacological inhibition of this inflammasome leads to reduced blood pressure in animal models and humans. Although the relationship between pyroptosis and hypertension is not well established yet, pyroptosis has been associated with renal and cardiovascular diseases, instances where high blood pressure is a critical risk factor. In this review, we summarize the recent literature addressing the role of pyroptosis and the inflammasome in the development of hypertension and discuss the potential use of approaches targeting this pathway as future anti-hypertensive strategies.
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Susceptibilidad a Enfermedades , Hipertensión/genética , Hipertensión/metabolismo , Inflamasomas/metabolismo , Piroptosis , Animales , Biomarcadores , Presión Sanguínea , Desarrollo de Medicamentos , Femenino , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Hipotálamo/metabolismo , Inflamación/complicaciones , Inflamación/metabolismo , Terapia Molecular Dirigida , Embarazo , Especies Reactivas de Oxígeno , Transducción de SeñalRESUMEN
DJ-1 is a redox-sensitive chaperone with reported antioxidant and anti-inflammatory properties in the kidney. The 20 amino acid (aa) peptide ND-13 consists of 13 highly conserved aas from the DJ-1 sequence and a TAT-derived 7 aa sequence that helps in cell penetration. This study aimed to determine if ND-13 treatment prevents the renal damage and inflammation associated with unilateral ureter obstruction (UUO). Male C57Bl/6 and DJ-1-/- mice underwent UUO and were treated with ND-13 or vehicle for 14 days. ND-13 attenuated the renal expression of fibrotic markers TGF-ß and collagen1a1 (Col1a1) and inflammatory markers TNF-α and IL-6 in C57Bl/6 mice. DJ-1-/- mice treated with ND-13 presented similar decreased expression of TNF-α, IL-6 and TGF-ß. However, in contrast to C57Bl/6 mice, ND-13 failed to prevent renal fibrosis or to ameliorate the expression of Col1a1 in this genotype. Further, UUO led to elevated urinary levels of the proximal tubular injury marker neutrophil gelatinase-associated lipocalin (NGAL) in DJ-1-/- mice, which were blunted by ND-13. Our results suggest that ND-13 protects against UUO-induced renal injury, inflammation and fibrosis. These are all crucial mechanisms in the pathogenesis of kidney injury. Thus, ND-13 may be a new therapeutic approach to prevent renal diseases.
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Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Inflamación/tratamiento farmacológico , Fragmentos de Péptidos/uso terapéutico , Sustancias Protectoras/uso terapéutico , Proteína Desglicasa DJ-1/uso terapéutico , Obstrucción Ureteral/tratamiento farmacológico , Animales , Biomarcadores/metabolismo , Colágeno Tipo I/metabolismo , Cadena alfa 1 del Colágeno Tipo I , Interleucina-6/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Within a given free-range flock, some hens prefer to spend the majority of their time in the shed (stayers), while others frequently access the range (rangers). Laying performance has been associated not only with the development of these sub-populations but also with different body weights (BW). The purpose of this study was to determine if range usage, BW or a combination of both is associated with energy metabolism and as such contribute to improved hen performance. Forty-eight Lohmann Brown hens at 74 wk of age were selected from a commercial free-range farm based on their BW and range usage over a 56-week period. Using a 2 × 2 factorial arrangement, hens were either classified as heavy (mean ± SEM; 2.01 ± 0.02 kg, n = 24) or light (1.68 ± 0.01 kg, n = 24), and also classified as rangers (accessed the range for 84.1% of available days, 242 ± 3.75 d; n = 24) or stayers (accessed the range for 7.17% of available days; 23.4 ± 6.08 d, n = 24). Stayers had significantly higher metabolizable energy (ME) intake per metabolic BW per d (0.852 vs. 0.798 MJ/kg BW0.75 per d; P = 0.025), higher heat production (0.637 vs. 0.607 MJ/kg BW0.75 per d; P = 0.005), higher heat increment (0.267 vs. 0.237 MJ/kg BW0.75 per d; P = 0.005) and retained more nitrogen (1.59 vs. 1.46 g/hen per d; P = 0.023) compared to the rangers. Light hens had significantly higher metabolic energy intake per metabolic BW (0.854 vs. 0.796 MJ/kg BW0.75 per d; P = 0.018), net energy (NE) intake (0.595 vs. 0.551 MJ/kg BW0.75 per d; P = 0.032), and retained energy (0.225 vs. 0.181 MJ/kg BW0.75 per d; P = 0.032), as well as lower heat production (0.936 vs. 1.003 MJ/hen per d; P = 0.002) compared to heavier hens. An interaction was observed across levels of analysis i.e. between light stayers and light rangers. The light rangers had significantly higher NE intake compared to the light stayers (9.77 vs. 9.27 MJ/kg BW0.75 per d; P = 0.024). In conclusion, light hens were more energy efficient compared to heavy hens. Moreover, light rangers had a more efficient feed utilisation compared to the light stayers.
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Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D5 receptor (D5 R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1-/- mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT1 R), NADPH oxidase (NOX) subunits, D5 R, and NaCl cotransporter. Basal reactive oxygen species (ROS), NOX activity, and blood pressure (BP) were also higher in Snx1-/- mice, which were normalized by apocynin, a drug that prevents NOX assembly. Renal proximal tubule (RPT) cells from hypertensive (HT) Euro-American males had deficient SNX1 activity, impaired D5 R endocytosis, and increased ROS compared with cells from normotensive (NT) Euro-American males. siRNA-mediated depletion of SNX1 in RPT cells from NT subjects led to a blunting of D5 R agonist-induced increase in cAMP production and decrease in Na+ transport, effects that were normalized by over-expression of SNX1. Among HT African-Americans, three of the 12 single nucleotide polymorphisms interrogated for the SNX1 gene were associated with a decrease in systolic BP in response to hydrochlorothiazide (HCTZ). The results illustrate a new paradigm for the development of hypertension and imply that the trafficking protein SNX1 may be a crucial determinant for hypertension and response to antihypertensive therapy.
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Hipertensión/metabolismo , Estrés Oxidativo/fisiología , Nexinas de Clasificación/metabolismo , Animales , Presión Sanguínea/fisiología , Línea Celular , Femenino , Humanos , Riñón/metabolismo , Túbulos Renales Proximales/metabolismo , Masculino , Ratones , NADPH Oxidasas/metabolismo , Oxidación-Reducción , Transporte de Proteínas/fisiología , ARN Interferente Pequeño/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptor de Angiotensina Tipo 1/metabolismoRESUMEN
Effective receptor signaling is anchored on the preferential localization of the receptor in lipid rafts, which are plasma membrane platforms replete with cholesterol and sphingolipids. We hypothesized that the dopamine D1 receptor (D1 R) contains structural features that allow it to reside in lipid rafts for its activity. Mutation of C347 palmitoylation site and Y218 of a newly identified Cholesterol Recognition Amino Acid Consensus motif resulted in the exclusion of D1 R from lipid rafts, blunted cAMP response, impaired sodium transport, and increased oxidative stress in renal proximal tubule cells (RPTCs). Kidney-restricted silencing of Drd1 in C57BL/6J mice increased blood pressure (BP) that was normalized by renal tubule-restricted rescue with D1 R-wild-type but not the mutant D1 R 347A that lacks a palmitoylation site. Kidney-restricted disruption of lipid rafts by ß-MCD jettisoned the D1 R from the brush border, decreased sodium excretion, and increased oxidative stress and BP in C57BL/6J mice. Deletion of the PX domain of the novel D1 R-binding partner sorting nexin 19 (SNX19) resulted in D1 R partitioning solely to non-raft domains, while silencing of SNX19 impaired D1 R function in RPTCs. Kidney-restricted silencing of Snx19 resulted in hypertension in C57BL/6J mice. Our results highlight the essential role of lipid rafts for effective D1 R signaling.
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Riñón/metabolismo , Microdominios de Membrana/metabolismo , Receptores de Dopamina D1/metabolismo , Animales , Sitios de Unión/genética , Presión Sanguínea/genética , Presión Sanguínea/fisiología , Células Cultivadas , AMP Cíclico/metabolismo , Silenciador del Gen , Humanos , Túbulos Renales Proximales/metabolismo , Lipoilación , Masculino , Ratones , Ratones Endogámicos C57BL , Mutagénesis Sitio-Dirigida , Estrés Oxidativo , Receptores de Dopamina D1/deficiencia , Receptores de Dopamina D1/genética , Sodio/metabolismoRESUMEN
Background The regulation of sodium excretion is important in the pathogenesis of hypertension and salt sensitivity is predictive of cardiovascular events and mortality. C57Bl/6 and BALB/c mice have different blood pressure sensitivities to salt intake. High salt intake increases blood pressure in some C57Bl/6J mouse strains but not in any BALB/c mouse strain. Methods and Results We determined the cause of the difference in salt sensitivity between C57Bl/6 and BALB/c mice. Basal levels of superoxide and H2O2 were higher in renal proximal tubule cells (RPTCs) from BALB/c than C57Bl/6J mice. High salt diet increased H2O2 production in kidneys from BALB/c but C57Bl/6J mice. High sodium concentration (170 mmol/L) in the incubation medium increased H2O2 levels in BALB/c-RPTCs but not in C57Bl/6J-RPTCs. H2O2 (10 µmol/L) treatment decreased sodium transport in RPTCs from BALB/c but not C57Bl/6J mice. Overexpression of catalase in the mouse kidney predisposed BALB/c mice to salt-sensitive hypertension. Conclusions Our data show that the level of salt-induced H2O2 production negatively regulates RPTC sodium transport and determines the state of salt sensitivity in 2 strains of mice. High concentrations of antioxidants could prevent H2O2 production in renal proximal tubules, which would result in sodium retention and increased blood pressure.
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Presión Sanguínea , Peróxido de Hidrógeno/metabolismo , Hipertensión/prevención & control , Túbulos Renales Proximales/metabolismo , Estrés Oxidativo , Cloruro de Sodio Dietético , Animales , Catalasa/genética , Catalasa/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Hipertensión/etiología , Hipertensión/metabolismo , Hipertensión/fisiopatología , Túbulos Renales Proximales/fisiopatología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Eliminación Renal , Especificidad de la EspecieRESUMEN
Gastrin, secreted by stomach G cells in response to ingested sodium, stimulates the renal cholecystokinin B receptor (CCKBR) to increase renal sodium excretion. It is not known how dietary sodium, independent of food, can increase gastrin secretion in human G cells. However, fenofibrate (FFB), a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, increases gastrin secretion in rodents and several human gastrin-secreting cells, via a gastrin transcriptional promoter. We tested the following hypotheses: (1.) the sodium sensor in G cells plays a critical role in the sodium-mediated increase in gastrin expression/secretion, and (2.) dopamine, via the D1R and PPAR-α, is involved. Intact human stomach antrum and G cells were compared with human gastrin-secreting gastric and ovarian adenocarcinoma cells. When extra- or intracellular sodium was increased in human antrum, human G cells, and adenocarcinoma cells, gastrin mRNA and protein expression/secretion were increased. In human G cells, the PPAR-α agonist FFB increased gastrin protein expression that was blocked by GW6471, a PPAR-α antagonist, and LE300, a D1-like receptor antagonist. LE300 prevented the ability of FFB to increase gastrin protein expression in human G cells via the D1R, because the D5R, the other D1-like receptor, is not expressed in human G cells. Human G cells also express tyrosine hydroxylase and DOPA decarboxylase, enzymes needed to synthesize dopamine. G cells in the stomach may be the sodium sensor that stimulates gastrin secretion, which enables the kidney to eliminate acutely an oral sodium load. Dopamine, via the D1R, by interacting with PPAR-α, is involved in this process.
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Gastrinas/metabolismo , Neoplasias Ováricas/metabolismo , PPAR alfa/metabolismo , Antro Pilórico/metabolismo , Receptores de Dopamina D1/metabolismo , Línea Celular , Línea Celular Tumoral , Células Cultivadas , Femenino , Fenofibrato/farmacología , Técnica del Anticuerpo Fluorescente , Células Secretoras de Gastrina/efectos de los fármacos , Células Secretoras de Gastrina/metabolismo , Humanos , Inmunohistoquímica , Fitohemaglutininas/metabolismo , Antro Pilórico/efectos de los fármacos , ARN Mensajero/metabolismo , Receptores de Dopamina D1/agonistas , Cloruro de Sodio/farmacologíaRESUMEN
Background The redox-sensitive chaperone DJ -1 and uncoupling protein 2 are protective against mitochondrial oxidative stress. We previously reported that renal-selective depletion and germline deletion of DJ -1 increases blood pressure in mice. This study aimed to determine the mechanisms involved in the oxidative stress-mediated hypertension in DJ -1 -/- mice. Methods and Results There were no differences in sodium excretion, renal renin expression, renal NADPH oxidase activity, and serum creatinine levels between DJ -1 -/- and wild-type mice. Renal expression of nitro-tyrosine, malondialdehyde, and urinary kidney injury marker-1 were increased in DJ -1 -/- mice relative to wild-type littermates. mRNA expression of mitochondrial heat shock protein 60 was also elevated in kidneys from DJ -1 -/- mice, indicating the presence of oxidative stress. Tempol-treated DJ -1 -/- mice presented higher serum nitrite/nitrate levels than vehicle-treated DJ -1 -/- mice, suggesting a role of the NO system in the high blood pressure of this model. Tempol treatment normalized renal kidney injury marker-1 and malondialdehyde expression as well as blood pressure in DJ -1 -/- mice, but had no effect in wild-type mice. The renal Ucp2 mRNA expression was increased in DJ -1 -/- mice versus wild-type and was also normalized by tempol. The renal-selective silencing of Ucp2 led to normalization of blood pressure and serum nitrite/nitrate ratio in DJ -1 -/- mice. Conclusions The deletion of DJ -1 leads to oxidative stress-induced hypertension associated with downregulation of NO function, and overexpression of Ucp2 in the kidney increases blood pressure in DJ -1 -/- mice. To our knowledge, this is the first report providing evidence of the role of uncoupling protein 2 in blood pressure regulation.
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Presión Sanguínea , Hipertensión/enzimología , Riñón/enzimología , Proteína Desglicasa DJ-1/deficiencia , Proteína Desacopladora 2/metabolismo , Animales , Chaperonina 60/genética , Chaperonina 60/metabolismo , Modelos Animales de Enfermedad , Hipertensión/genética , Hipertensión/fisiopatología , Riñón/fisiopatología , Masculino , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Óxido Nítrico/metabolismo , Estrés Oxidativo , Proteína Desglicasa DJ-1/genética , Transducción de Señal , Proteína Desacopladora 2/genética , Regulación hacia ArribaRESUMEN
Hypertension is the most prevalent cause of cardiovascular disease and kidney failure, but only about 50% of patients achieve adequate blood pressure control, in part, due to inter-individual genetic variations in the response to antihypertensive medication. Significant strides have been made toward the understanding of the role of reactive oxygen species (ROS) in the regulation of the cardiovascular system. However, the role of ROS in human hypertension is still unclear. Polymorphisms of some genes involved in the regulation of ROS production are associated with hypertension, suggesting their potential influence on blood pressure control and response to antihypertensive medication. This review provides an update on the genes associated with the regulation of ROS production in hypertension and discusses the controversies on the use of antioxidants in the treatment of hypertension, including the antioxidant effects of antihypertensive drugs.
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Presión Sanguínea/genética , Polimorfismo Genético/genética , Especies Reactivas de Oxígeno/metabolismo , Animales , Antioxidantes/metabolismo , Humanos , Hipertensión/genética , Hipertensión/metabolismoRESUMEN
An immunophenotyping analysis was performed in peripheral blood samples from seven patients with lung cancer unfit for surgery treated with stereotactic body radiotherapy (SBRT). The objective was to characterize the effect of SBRT on the host immune system. Four patients received 60 Gy (7.5 Gy × 8) and three 50 Gy (12.5 Gy × 4). Analyses were performed before SBRT, 72 h after SBRT, and at one, three, and six months after the end of SBRT. Of note, there was a specific increase of the immunoactive component of the immune system, with elevation of CD56+highCD16+ natural killer (NK) cells (0.95% at baseline to 1.38% at six months), and a decrease of the immunosuppressive component of the immune system, with decreases of CD4+CD25+Foxp3+CDA5RA- regulatory T cells (4.97% at baseline to 4.46% at six months), granulocytic myeloid-derived suppressor cells (G-MDSCs) (from 66.1% at baseline to 62.6% at six months) and monocytic (Mo-MDSCs) (8.2% at baseline to 6.2% at six months). These changes were already apparent at 72 h and persisted over six months. SBRT showed an effect on systemic immune cell populations, which is a relevant finding for supporting future combinations of SBRT with immunotherapy for treating lung cancer patients.