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Background. Folate therapy reduces, but does not normalize homocysteine (Hcy) levels, frequently elevated in chronic kidney disease (CKD). The mechanisms of this folate resistance are unknown. Cellular acquisition of folate is mediated by folate receptors (FRs), whose expression is also modulated by folate status, through an Hcy-dependent regulation mechanism involving heterogeneous nuclear ribonucleoprotein-E1 (hnRNP-E1). Our objective was to evaluate whether an alteration of the FR2 (the form present in nucleated blood cells) expression is present in CKD patients on hemodialysis (HD), and its susceptibility to folate treatment. Methods. A population of chronic uremic patients on HD was enrolled, along with a control group, and studies on FR2 receptor expression and related items were performed in plasma and mononuclear cells from peripheral blood. A subgroup of patients was treated with ev methyltetrahydrofolate for one month. Results. In HD, there was a significant reduction in FR2 protein expression compared to controls, not correlated with Hcy concentrations, while its mRNA levels were significantly increased. After folate treatment, there was a significant mRNA decrease, in the absence of significant changes in receptor protein expression. hnRNP-E1 gene and protein expression levels increased pre-treatment, while decreased post-treatment. Conclusions. In HD, FR2 expression is altered in peripheral mononuclear cells, since its levels are decreased and are not responsive to variations in Hcy concentration, while the intracellular machinery (receptor mRNA and hnRNP-E1), possibly triggering its regulation, is conserved. These findings provide insight into the mechanisms of folate resistance in uremia. Background Folate therapy reduces, but does not normalize homocysteine (Hcy) levels, frequently elevated in chronic kidney disease (CKD). The mechanisms of this folate resistance are unknown. Cellular acquisition of folate is mediated by folate receptors (FRs), whose expression is also modulated by folate status, through an Hcy-dependent regulation mechanism involving heterogeneous nuclear ribonucleoprotein-E1 (hnRNP-E1). Our objective was to evaluate whether an alteration of the FR2 (the form present in nucleated blood cells) expression is present in CKD patients on haemodialysis (HD), and its susceptibility to folate treatment. Methods A population of chronic uraemic patients on HD was enrolled, along with a control group, and studies on FR2 receptor expression and related items were performed in plasma and mononuclear cells from peripheral blood. A subgroup of patients was treated with methyltetrahydrofolate for 1 month.ResultsIn HD, there was a significant reduction in FR2 protein expression compared with controls, not correlated with Hcy concentrations, while its mRNA levels were significantly increased. After folate treatment, there was a significant mRNA decrease, in the absence of significant changes in receptor protein expression. hnRNP-E1 gene and protein expression levels increased pre-treatment, while decreased post-treatment. Conclusions In HD, FR2 expression is altered in peripheral mononuclear cells, since its levels are decreased and are not responsive to variations in Hcy concentration, while the intracellular machinery (receptor mRNA and hnRNP-E1), possibly triggering its regulation, is conserved. These findings provide insight into the mechanisms of folate resistance in uraemia. © 2013 © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Hydrogen sulfide (H(2)S) is a poisonous gas which can be lethal. However, it is also produced endogenously, thus belonging to the family of gasotransmitters along with nitric oxide and carbon monoxide. H(2)S is in fact involved in mediating several signaling and cytoprotective functions, for example in the nervous, cardiovascular, and gastrointestinal systems, such as neuronal transmission, blood pressure regulation and insulin release, among others. When increased, it can mediate inflammation and apoptosis, with a role in shock. When decreased, it can be involved in atherosclerosis, hypertension, myocardial infarction, diabetes, sexual dysfunction, and gastric ulcer; it notably interacts with the other gaseous mediators. Cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase are the principal enzymes involved in H(2)S production. We have recently studied H(2)S metabolism in the plasma of chronic hemodialysis patients and reported that its levels are significantly decreased. The plausible mechanism lies in the transcription inhibition of the cystathionine γ-lyase gene. The finding could be of importance considering that hypertension and high cardiovascular mortality are characteristic in these patients. Hydrogen sulfide (H2S) is a poisonous gas which can be lethal. However, it is also produced endogenously, thus belonging to the family of gasotransmitters along with nitric oxide and carbon monoxide. H2S is in fact involved in mediating several signaling and cytoprotective functions, for example in the nervous, cardiovascular, and gastrointestinal systems, such as neuronal transmission, blood pressure regulation and insulin release, among others. When increased, it can mediate inflammation and apoptosis, with a role in shock. When decreased, it can be involved in atherosclerosis, hypertension, myocardial infarction, diabetes, sexual dysfunction, and gastric ulcer; it notably interacts with the other gaseous mediators. Cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase are the principal enzymes involved in H2S production. We have recently studied H2S metabolism in the plasma of chronic hemodialysis patients and reported that its levels are significantly decreased. The plausible mechanism lies in the transcription inhibition of the cystathionine γ-lyase gene. The finding could be of importance considering that hypertension and high cardiovascular mortality are characteristic in these patients. Copyright © 2011 S. Karger AG, Basel.

Hydrogen sulfide, H2S, is the third endogenous gas with cardiovascular properties, after nitric oxide and carbon monoxide. H2S is a potent vasorelaxant, and its deficiency is implicated in the pathogenesis of hypertension and atherosclerosis. Cystathionine beta-synthase, cystathionine gamma- lyase, and 3-mercaptopyruvate sulfurtransferase catalyze H2S formation. Chronic kidney disease is characterized by high prevalence of hyperhomocysteinemia, hypertension, and high cardiovascular mortality, especially in hemodialysis patients. H2S levels are decreased in hemodialysis patients through transcriptional deregulation of genes encoding for the H2S-producing enzymes. Potential implications relate to the pathogenesis of the manifestations of the uremic syndrome, such as hypertension and atherosclerosis. (C) 2010 by the National Kidney Foundation, Inc. All rights reserved.

Hyperhomocysteinemia is an independent cardiovascular risk factor, according to most observational studies and to studies using the Mendelian randomization approach, utilizing the common polymorphism C677T of methylene tetrahydrofolate reductase. In contrast, the most recent secondary preventive intervention studies, in the general population and in chronic kidney disease (CKD) and uremia, which are all negative (with the possible notable exception of stroke), point to other directions. However, all trials use folic acid in various dosages as a means to reduce homocysteine levels, with the addition of vitamins B6 and B12. It is possible that folic acid has negative effects, which offset the benefits; alternatively, homocysteine could be an innocent by-stander, or a surrogate of the real culprit. The latter possibility leads us to the search for potential candidates. First, the accumulation of homocysteine in blood leads to an intracellular increase of S-adenosylhomocysteine (AdoHcy), a powerful competitive methyltransferase inhibitor, which by itself is considered a predictor of cardiovascular events. DNA methyltransferases are among the principal targets of hyperhomocysteinemia, as studies in several cell culture and animal models, as well as in humans, show. In CKD and in uremia, hyperhomocysteinemia and high intracellular AdoHcy are present and are associated with abnormal allelic expression of genes regulated through methylation, such as imprinted genes, and pseudoautosomal genes, thus pointing to epigenetic dysregulation. These alterations are susceptible to reversal upon homocysteine-lowering therapy obtained through folate administration. Second, it has to be kept in mind that homocysteine is mainly protein-bound, and its effects could be linked therefore to protein homocysteinylation. In this respect, increased protein homocysteinylation has been found in uremia, leading to alterations in protein function. © 2009 Wiley Periodicals, Inc.

Background. Hydrogen sulphide, H2S, is the third endogenous gas with putative cardiovascular properties, after nitric oxide and carbon monoxide. H2S is a vasorelaxant, while H2S deficiency is implicated in the pathogenesis of hypertension and atherosclerosis. Cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulphurtransferase (MPS) catalyze H2S formation, with different relative efficiencies. Chronic kidney disease (CKD) is characterized by elevation of both plasma homocysteine and cysteine, which are substrates of these enzymes, and by a high prevalence of hypertension and cardiovascular mortality, particularly in the haemodialysis stage. It is possible that the H2S-generating pathways are altered as well in this patient population. Methods. Plasma H2S levels were measured with a common spectrophotometric method. This method detects various forms of H2S, protein-bound and non-protein-bound. Blood sulphaemoglobin, a marker of chronic exposure to H2S, was also measured, as well as related sulphur amino acids, vitamins and transcriptional levels of relevant genes, in haemodialysis patients and compared to healthy controls. Results. Applying the above-mentioned methodology, H2S levels were found to be decreased in patients. Sulphaemoglobin levels were significantly lower as well. Plasma homocysteine and cysteine were significantly higher; vitamin B6, a cofactor in H2S biosynthesis, was not different. H2S correlated negatively with cysteine levels. CSE expression was significantly downregulated in haemodialysis patients. Conclusions. Transcriptional deregulation of genes encoding for H2S-producing enzymes is present in uraemia. Although the specificity of the method employed for H2S detection is low, the finding that H2S is decreased is complemented by the lower sulphhaemoglobin levels. Potential implications of this study relate to the pathogenesis of the uraemic syndromemanifestations, such as hypertension and atherosclerosis. Background. Hydrogen sulphide, H2S, is the third endogenous gas with putative cardiovascular properties, after nitric oxide and carbon monoxide. H2S is a vasorelaxant, while H2S deficiency is implicated in the pathogenesis of hypertension and atherosclerosis. Cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE) and 3-mercaptopyruvate sulphurtransferase (MPS) catalyze H2S formation, with different relative efficiencies. Chronic kidney disease (CKD) is characterized by elevation of both plasma homocysteine and cysteine, which are substrates of these enzymes, and by a high prevalence of hypertension and cardiovascular mortality, particularly in the haemodialysis stage. It is possible that the H2S-generating pathways are altered as well in this patient population.Methods. Plasma H2S levels were measured with a common spectrophotometric method. This method detects various forms of H2S, protein-bound and non-protein-bound. Blood sulphaemoglobin, a marker of chronic exposure to H2S, was also measured, as well as related sulphur amino acids, vitamins and transcriptional levels of relevant genes, in haemodialysis patients and compared to healthy controls.Results. Applying the above-mentioned methodology, H2S levels were found to be decreased in patients. Sulphaemoglobin levels were significantly lower as well. Plasma homocysteine and cysteine were significantly higher; vitamin B-6, a cofactor in H2S biosynthesis, was not different. H2S correlated negatively with cysteine levels. CSE expression was significantly downregulated in haemodialysis patients.Conclusions. Transcriptional deregulation of genes encoding for H2S-producing enzymes is present in uraemia. Although the specificity of the method employed for H2S detection is low, the finding that H2S is decreased is complemented by the lower sulphhaemoglobin levels. Potential implications of this study relate to the pathogenesis of the uraemic syndrome manifestations, such as hypertension and atherosclerosis.