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Background: Brugada syndrome (BrS) is an inherited primary channelopathy syndrome associated with the risk of ventricular fibrillation (VF) and sudden cardiac death in a structurally normal heart. Aim of the Study: The aim of this study was to clinically and genetically evaluate a large family with severe autosomal dominant Brugada syndrome. Methods: Clinical and genetic studies were performed. Genetic analysis was conducted with NGS technologies (WES) using the Illumina instrument. According to the standard procedure, variants found by WES were confirmed in all available families by Sanger sequencing. The effect of the variants was studied by using in silico prediction of pathogenicity. Results: The proband was a 52-year-old man who was admitted to the emergency department for syncope at rest. WES of the index case identified a heterozygous VUS CASQ2, c.532T>C, p.(Tyr178His). We studied the segregation of the variation in all pedigree members. All the patients were heterozygous for the variation CASQ2 p.(Tyr178His), whereas the remaining healthy individuals in the family were homozygous for the normal allele. Structural analysis of CASQ2 p.(Tyr178His) was performed and revealed an important effect of the missense variation on monomer stability. The CASQ2 Tyr180 residue is located inside the sarcoplasmic reticulum (SR) junctional face membrane interaction domain and is predicted to disrupt filamentation. Conclusions: Our data suggest that the p.Tyr178His substitution is associated with BrS in the family investigated, affecting the stability of the protein, disrupting filamentation at the interdimer interface, and affecting the subsequent formation of tetramers and polymers that contain calcium-binding sites. [ABSTRACT FROM AUTHOR]

The mechanisms underlying obesity-related kidney disease are not well understood. Growing evidence suggests that free fatty acids, a cause of oxidative stress, play an important role in obesity and its related complications. So, we decided to investigate, in a human-conditioned immortalized podocyte cell line, the capacity of physiopathological concentrations of 27nM of nonconjugated palmitate to induce intracellular reactive oxygen species (ROS) production, podocytes endoplasmic reticulum stress, podocytes inflammation, and mitochondrial dysfunction. A conditionally immortalized human podocyte cell line was exposed to different percentages of palmitate conjugated to bovine serum albumin for 24h. We observed that palmitate, at the same concentrations seen in obese patients, caused overproduction of ROS in human podocytes and this oxidative stress induces dysfunctions in podocytes like inflammation and changes in profibrotic and lipotoxic markers. Highmobility group box 1 is likely known to be a major mediator of ROS damaging effects, as its pharmacological inhibition prevents all ROS effects on podocytes. Our study shows how, in podocytes, an unbounded fraction of 27nM of palmitate can induce dysfunctions similar to that observed in obesity-related glomerulopathy (ORG). These results could contribute to elucidating underlying mechanisms contributing to the ORG pathogenesis. [ABSTRACT FROM AUTHOR]

Vascular permeability is an innate function of the circulatory system that regulates the flux of fluid, proteins, and immune cells from blood to tissue. Vascular permeability is regulated by a molecular mechanism that involves the endothelial barrier. Endothelial barrier function and vascular permeability are regulated by intercellular junctions that control the extravasation of plasma and its macromolecular constituents. The number and arrangement of these junctions determine permeability differences in the vasculature in an organ- and tissue-specific manner. The barrier is mediated by endothelial cell-cell adhesions. Adjacent endothelial cells are connected by protein complexes that are part of the Gap junctions (GJs), adherens junctions (AJs), Tight junctions (TJs), and additional other adhesion receptors such as CD31/Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) and nectins, which are connected to the actin cytoskeleton via different adaptor molecules. This review focuses on the molecular organization and regulation of endothelial junctions in vascular permeability in health and disease. Additional work should also be directed to the understanding of mechanisms that influence altered vascular permeability in specific diseases and to strategies for preventing or reversing vascular leakage, which can result in harmful consequences. [ABSTRACT FROM AUTHOR]

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The article focuses on how free fatty acids (FFAs), particularly palmitate, can induce oxidative stress, podocyte dysfunction, inflammation, and lipid metabolic memory in obesity-related glomerulopathy (ORG), shedding light on the mechanisms linking obesity with kidney pathology.

Urea at post-dialysis levels induces increased ROS in a number of cell types. The aim of this study was to determine whether urea-induced production of ROS remains elevated after urea is no longer present, and, if it does, to characterize its origin and effects. Human arterial endothelial cells were incubated with 20 mM urea for two days, and then cells were incubated for an additional two days in medium alone. Maximal ROS levels induced by initial urea continued at the same level despite urea being absent. These effects were prevented by either MnSOD expression or by Nox1/4 inhibition with GKT13781. Sustained urea-induced ROS caused a persistent reduction in mtDNA copy number and electron transport chain transcripts, a reduction in transcription of mitochondrial fusion proteins, an increase in mitochondrial fission proteins, and persistent expression of endothelial inflammatory markers. The SOD-catalase mimetic MnTBAP reversed each of these. These results suggest that persistent increases in ROS after cells are no long exposed to urea may play a major role in continued kidney damage and functional decline despite reduction of urea levels after dialysis. [ABSTRACT FROM AUTHOR]

The pathogenic events responsible for accelerated atherosclerosis in patients with chronic renal failure (CRF) are poorly understood [2]. Here we investigate the hypothesis that concentrations of urea associated with CRF and increased ROS production in adipocytes3 might also increase ROS production directly in arterial endothelial cells, causing the same pathophysiologic changes seen with hyperglycemia [1]. For these purpose, confluent primary human aortic endothelial cells (HAECs) were incubated with either 20mM urea or with 20mM mannitol used as osmotic control, for 48 hours. Urea induces mitochondrial reactive oxygen species in HAEC and cause pro-inflammatory changes in endothelial cells. Breafly, PGI2 Synthase activity, NFκB p65 and NFκB-specific target genes mRNA expression (MCP-1 and VCAM-1) [3] and their protein levels were evaluated. Moreover, we have shown that urea-induced ROS production increases PKC activity, hexosamine pathway activity and intracellular AGE formation in HAEC. In addition, urea-induced ROS decrease GAPDH activity, increase DNA strand breaks and increase PARP activity in HAEC. In summary, urea increases mitochondrial ROS production in arterial endothelial cells, thereby activating pro-atherosclerotic pathways and directly inactivating PGI2 synthase, a critical endothelial-specific antiatherosclerotic enzyme in vitro. The present findings provide further insight into the underlying mechanisms that contribute to the enhanced cardiovascular risk associated with chronic renal failure. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is one of the leading contributors to morbidity and mortality in chronic renal failure (CRF) patients. Endothelial injury caused by various cardiovascular risk factors is a responsable for atherosclerosis [1]. In uremic patients, evidence of endothelial dysfunction has been identified at early stages of the disease [2]. Endothelial progenitor cells (EPCs) play a key role in the maintenance of vascular integrity by promoting endothelial repair mechanisms and new endothelial growth. Uremia and compromised renal function are associated with a greater reduction in EPC availability and function [3]. Here we investigate the hypothesis that increased concentrations of urea associated with CRF increase ROS production directly in EPCs, causing abnormalities associated with coronary artery disease risk. Human EPCs were isolated from peripheral blood mononuclear cells of healthy donors and cultured in the presence or absence of 20 mmol/L urea. Urea, at concentrations seen in CRF, induces reactive oxygen species production in endothelial progenitor cells through the activation of mitochondrial and cytosolic mechanisms. Urea-induced ROS production impairs EC-CFU morphology and number, reduced the uptake and binding of Dil-Ac-LDL and lectin-1, and the ability to differentiate into CD31- and vascular endothelial growth factor receptor 2 positive cells. Moreover, urea-induced ROS generation accelerated the onset of EPC senescence, leading to a senescence-associated secretory phenotype (SASP). Normalization of mitochondrial ROS production prevented each of these effects of urea. These data suggest that urea itself causes both reduced EPC number and increased EPC dysfunction, thereby contributing to the pathogenesis of cardiovascular disease in CRF patients. [ABSTRACT FROM AUTHOR]

Obesity is a social and economical problem. The prevalence of obesity has risen to epidemic proportions and continues to be one of the major worldwide health problem. Concurrent with the global obesity epidemic, there is an increasing number of people of all ages developing chronic kidney disease associated with obesity(1). Although obesity is often associated with diabetes and hypertension, which are two of the most common risk factors for the development of end-stage renal disease (ESRD), obesity in itself can be an independent risk factor for both chronic kidney disease (CKD) and ESRD. The signaling pathways leading to renal pathology in obesity are not well understood. Here we investigate the hypothesis that physio-pathological concentration of palmitate induces reactive oxygen species production in conditioned human podocytes cell line through the activation of mitochondrial mechanisms, induces endoplasmic reticulum (ER) stress and increases HMGB1 expression and inflammation. The conditionally immortalized human podocytes cell line were differentiated and then treated with/without palmitate conjugated with BSA in a control and physio-pathological condition(2) and cell morphology, under sperimental conditions, were evaluated. Physio-pathological palmitate concentrations stimulate ROS generation in human podocyte and induces endoplasmic reticulum (ER) stress in podocytes. Moreover palmitate- induced ROS caused the activation of pro-inflammatory pathways (p65/NfkB and MCP-1), up-regulation of TGF-ß well identified as a central mediator in renal fibrosis and induces a significantly increase of gene expression of HMGB1. Normalization of mitochondrial ROS production prevented each of these effects of palmitate. These results showed that palmitate at physio-pathological concentrations is able to induce ROS production, ER stress, inflammation, fibrosis and dysregulation of HMGB1 in human podocytes. [ABSTRACT FROM AUTHOR]

Chronic kidney disease in children is an irreversible process that may lead to end-stage renal disease. The mortality rate in children with end-stage renal disease who receive dialysis increased dramatically in the last decade, and it is significantly higher compared with the general pediatric population. Furthermore, dialysis and transplant patients, who have developed end-stage renal disease during childhood, live respectively far less as compared with age/race-matched populations. Different reports show that cardiovascular disease is the leading cause of death in children with end-stage renal disease and in adults with childhood-onset chronic kidney disease, and that children with chronic kidney disease are in the highest risk group for the development of cardiovascular disease. Urea, which is generated in the liver during catabolism of amino acids and other nitrogenous metabolites, is normally excreted into the urine by the kidneys as rapidly as it is produced. When renal function is impaired, increasing concentrations of blood urea will steadily accumulate. For a long time, urea has been considered to have negligible toxicity. However, the finding that plasma urea is the only significant predictor of aortic plaque area fraction in an animal model of chronic renal failure -accelerated atherosclerosis, suggests that the high levels of urea found in chronic dialysis patients might play an important role in accelerated atherosclerosis in this group of patients. The aim of this review was to provide novel insights into the role played by urea in the pathogenesis of accelerated cardiovascular disease in renal failure., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors.