Uremic Toxin

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Toshimitsu Niwa - One of the best experts on this subject based on the ideXlab platform.

  • RESEARCH ARTICLE Open Access Indoxyl sulfate, a Uremic Toxin, downregulates
    2016
    Co-Authors: Graduatedilinaer Bolati, Fuyuhiko Nishijima, Hidehisa Shimizu, Maimaiti Yisireyili, Toshimitsu Niwa
    Abstract:

    Background: Indoxyl sulfate, a Uremic Toxin, is accumulated in the serum of chronic kidney disease (CKD) patients, accelerating the progression of CKD. In CKD rat kidney, the expressions of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its related genes are downregulated. AST-120, an oral sorbent, reduces serum indoxyl sulfate and slows the progression of CKD. The present study aimed to determine whether indoxyl sulfate downregulates Nrf2 expression in human proximal tubular cells and rat kidneys and whether AST-120 upregulates Nrf2 expression in CKD rat kidneys. Methods: Effects of indoxyl sulfate on expression of Nrf2 were determined using HK-2 cells as human proximal tubular cells and the following animals: (1) Dahl salt-resistant normotensive rats (DN), (2) Dahl salt-resistant normotensive indoxyl sulfate-administered rats (DN+IS), (3) Dahl salt-sensitive hypertensive rats (DH), and (4) Dahl salt-sensitive hypertensive indoxyl sulfate-administered rats (DH+IS). Further, AST-120 was administered to subtotally nephrectomized CKD rats to determine its effect on the expression of Nrf2. Results: Indoxyl sulfate downregulated Nrf2 expression in HK-2 cells. The indoxyl sulfate-induced downregulation of Nrf2 expression was alleviated by an inhibitor of nuclear factor-κB (NF-κB) (pyrrolidine dithiocarbamate) and small interfering RNA specific to NF-κB p65. DN+IS, DH, and DH+IS rats showed decreased renal expression of Nrf2 an

  • indoxyl sulfate induced activation of pro renin receptor promotes cell proliferation and tissue factor expression in vascular smooth muscle cells
    PLOS ONE, 2014
    Co-Authors: Maimaiti Yisireyili, Toshimitsu Niwa, Fuyuhiko Nishijima, Shinichi Saito, Shaniya Abudureyimu, Yelixiati Adelibieke, Kyosuke Takeshita, Toyoaki Murohara
    Abstract:

    Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease (CVD). (Pro)renin receptor (PRR) is activated in the kidney of CKD. The present study aimed to determine the role of indoxyl sulfate (IS), a Uremic Toxin, in PRR activation in rat aorta and human aortic smooth muscle cells (HASMCs). We examined the expression of PRR and renin/prorenin in rat aorta using immunohistochemistry. Both CKD rats and IS-administrated rats showed elevated expression of PRR and renin/prorenin in aorta compared with normal rats. IS upregulated the expression of PRR and prorenin in HASMCs. N-acetylcysteine, an antioxidant, and diphenyleneiodonium, an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase, suppressed IS-induced expression of PRR and prorenin in HASMCs. Knock down of organic anion transporter 3 (OAT3), aryl hydrocarbon receptor (AhR) and nuclear factor-κB p65 (NF-κB p65) with small interfering RNAs inhibited IS-induced expression of PRR and prorenin in HASMCs. Knock down of PRR inhibited cell proliferation and tissue factor expression induced by not only prorenin but also IS in HASMCs.

  • creb nf κb and nadph oxidase coordinately upregulate indoxyl sulfate induced angiotensinogen expression in proximal tubular cells
    American Journal of Physiology-cell Physiology, 2013
    Co-Authors: Hidehisa Shimizu, Fuyuhiko Nishijima, Shinichi Saito, Yukihiro Higashiyama, Toshimitsu Niwa
    Abstract:

    In chronic kidney disease (CKD), indoxyl sulfate, a Uremic Toxin, accumulates in serum, and the expression of angiotensinogen (AGT) is upregulated in renal proximal tubular cells. The present study...

  • indoxyl sulfate promotes vascular smooth muscle cell senescence with upregulation of p53 p21 and prelamin a through oxidative stress
    American Journal of Physiology-cell Physiology, 2012
    Co-Authors: Gulinuer Muteliefu, Hidehisa Shimizu, Fuyuhiko Nishijima, Atsushi Enomoto, Masahide Takahashi, Toshimitsu Niwa
    Abstract:

    We previously demonstrated that indoxyl sulfate (IS), a Uremic Toxin, induces aortic calcification in hypertensive rats and induces oxidative stress and the expression of osteoblast-specific protei...

  • indoxyl sulfate induces epithelial to mesenchymal transition in rat kidneys and human proximal tubular cells
    American Journal of Nephrology, 2011
    Co-Authors: Dilinaer Bolati, Fuyuhiko Nishijima, Hidehisa Shimizu, Yukihiro Higashiyama, Toshimitsu Niwa
    Abstract:

    Background/Aims: Indoxyl sulfate (IS) is a Uremic Toxin that accelerates the progression of chronic kidney disease (CKD). This study aimed to determine if IS induces epithelial-to-m

Fuyuhiko Nishijima - One of the best experts on this subject based on the ideXlab platform.

  • RESEARCH ARTICLE Open Access Indoxyl sulfate, a Uremic Toxin, downregulates
    2016
    Co-Authors: Graduatedilinaer Bolati, Fuyuhiko Nishijima, Hidehisa Shimizu, Maimaiti Yisireyili, Toshimitsu Niwa
    Abstract:

    Background: Indoxyl sulfate, a Uremic Toxin, is accumulated in the serum of chronic kidney disease (CKD) patients, accelerating the progression of CKD. In CKD rat kidney, the expressions of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its related genes are downregulated. AST-120, an oral sorbent, reduces serum indoxyl sulfate and slows the progression of CKD. The present study aimed to determine whether indoxyl sulfate downregulates Nrf2 expression in human proximal tubular cells and rat kidneys and whether AST-120 upregulates Nrf2 expression in CKD rat kidneys. Methods: Effects of indoxyl sulfate on expression of Nrf2 were determined using HK-2 cells as human proximal tubular cells and the following animals: (1) Dahl salt-resistant normotensive rats (DN), (2) Dahl salt-resistant normotensive indoxyl sulfate-administered rats (DN+IS), (3) Dahl salt-sensitive hypertensive rats (DH), and (4) Dahl salt-sensitive hypertensive indoxyl sulfate-administered rats (DH+IS). Further, AST-120 was administered to subtotally nephrectomized CKD rats to determine its effect on the expression of Nrf2. Results: Indoxyl sulfate downregulated Nrf2 expression in HK-2 cells. The indoxyl sulfate-induced downregulation of Nrf2 expression was alleviated by an inhibitor of nuclear factor-κB (NF-κB) (pyrrolidine dithiocarbamate) and small interfering RNA specific to NF-κB p65. DN+IS, DH, and DH+IS rats showed decreased renal expression of Nrf2 an

  • indoxyl sulfate induced activation of pro renin receptor promotes cell proliferation and tissue factor expression in vascular smooth muscle cells
    PLOS ONE, 2014
    Co-Authors: Maimaiti Yisireyili, Toshimitsu Niwa, Fuyuhiko Nishijima, Shinichi Saito, Shaniya Abudureyimu, Yelixiati Adelibieke, Kyosuke Takeshita, Toyoaki Murohara
    Abstract:

    Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease (CVD). (Pro)renin receptor (PRR) is activated in the kidney of CKD. The present study aimed to determine the role of indoxyl sulfate (IS), a Uremic Toxin, in PRR activation in rat aorta and human aortic smooth muscle cells (HASMCs). We examined the expression of PRR and renin/prorenin in rat aorta using immunohistochemistry. Both CKD rats and IS-administrated rats showed elevated expression of PRR and renin/prorenin in aorta compared with normal rats. IS upregulated the expression of PRR and prorenin in HASMCs. N-acetylcysteine, an antioxidant, and diphenyleneiodonium, an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase, suppressed IS-induced expression of PRR and prorenin in HASMCs. Knock down of organic anion transporter 3 (OAT3), aryl hydrocarbon receptor (AhR) and nuclear factor-κB p65 (NF-κB p65) with small interfering RNAs inhibited IS-induced expression of PRR and prorenin in HASMCs. Knock down of PRR inhibited cell proliferation and tissue factor expression induced by not only prorenin but also IS in HASMCs.

  • creb nf κb and nadph oxidase coordinately upregulate indoxyl sulfate induced angiotensinogen expression in proximal tubular cells
    American Journal of Physiology-cell Physiology, 2013
    Co-Authors: Hidehisa Shimizu, Fuyuhiko Nishijima, Shinichi Saito, Yukihiro Higashiyama, Toshimitsu Niwa
    Abstract:

    In chronic kidney disease (CKD), indoxyl sulfate, a Uremic Toxin, accumulates in serum, and the expression of angiotensinogen (AGT) is upregulated in renal proximal tubular cells. The present study...

  • chronic kidney disease induced cardiac fibrosis is ameliorated by reducing circulating levels of a non dialysable Uremic Toxin indoxyl sulfate
    PLOS ONE, 2012
    Co-Authors: Suree Lekawanvijit, Fuyuhiko Nishijima, Andrew R Kompa, Minako Manabe, Bing H Wang, Robyn G Langham, Darren J Kelly, Henry Krum
    Abstract:

    Cardiovascular death commonly occurs in patients with chronic kidney disease. Indoxyl sulfate (IS), a Uremic Toxin, has been demonstrated in vitro as a contributory factor in cardiac fibrosis, a typical pathological finding in Uremic cardiomyopathy. This study aimed to determine if cardiac fibrosis is reversible by lowering serum IS levels using an oral charcoal adsorbent, AST-120. Subtotal-nephrectomized (5/6-STNx) Sprague-Dawley rats were randomized to receive either AST-120 (AST-120, n = 13) or no treatment (vehicle, n = 17) for 12 weeks. Sham operated rats (n = 12) were used as controls. Early left ventricular (LV) diastolic dysfunction was demonstrated by an increase in peak velocity of atrial filling [A and A’ waves] and a decrease of E/A and E’/A’ ratios obtained by echocardiography. This was accompanied by a 4.5-fold increase in serum IS (p<0.001) as well as elevated tail-cuff blood pressure (p<0.001) and heart weight (p<0.001). Increased LV fibrosis (p<0.001), gene expression of pro-fibrotic (TGF-β, CTGF) and hypertrophic (ANP, β-MHC and α-skeletal muscle actin) markers, as well as TGF-β and phosphorylated NF-κB protein expression were observed in STNx + vehicle rats. Treatment with AST-120 reduced serum creatinine (by 54%, p<0.05) and urine total protein (by 27%, p<0.05) vs vehicle whilst having no effect on blood pressure (AST-120 = 227±11 vs vehicle = 224±8 mmHg, ns) and heart weight. The increase in serum IS was prevented with AST-120 (by 100%, p<0.001) which was accompanied by reduced LV fibrosis (68%, p<0.01) and TGF-β and phosphorylated NF-κB protein expression (back to sham levels, p<0.05) despite no significant change in LV function. In conclusion, STNx resulted in increased cardiac fibrosis and circulating IS levels. Reduction of IS with AST-120 normalizes cardiac fibrosis, in a blood pressure independent manner.

  • indoxyl sulfate promotes vascular smooth muscle cell senescence with upregulation of p53 p21 and prelamin a through oxidative stress
    American Journal of Physiology-cell Physiology, 2012
    Co-Authors: Gulinuer Muteliefu, Hidehisa Shimizu, Fuyuhiko Nishijima, Atsushi Enomoto, Masahide Takahashi, Toshimitsu Niwa
    Abstract:

    We previously demonstrated that indoxyl sulfate (IS), a Uremic Toxin, induces aortic calcification in hypertensive rats and induces oxidative stress and the expression of osteoblast-specific protei...

Hidehisa Shimizu - One of the best experts on this subject based on the ideXlab platform.

Alessandra F. Perna - One of the best experts on this subject based on the ideXlab platform.

  • Uremic Toxin Lanthionine Interferes with the Transsulfuration Pathway, Angiogenetic Signaling and Increases Intracellular Calcium.
    International journal of molecular sciences, 2019
    Co-Authors: Carmela Vigorito, Miriam Zacchia, Francesco Trepiccione, Evgeniya Anishchenko, Diego Ingrosso, Patrizia Lombari, Luigi Mele, Giovanna Capolongo, Rosanna Capasso, Alessandra F. Perna
    Abstract:

    (1) The beneficial effects of hydrogen sulfide (H2S) on the cardiovascular and nervous system have recently been re-evaluated. It has been shown that lanthionine, a side product of H2S biosynthesis, previously used as a marker for H2S production, is dramatically increased in circulation in uremia, while H2S release is impaired. Thus, lanthionine could be classified as a novel Uremic Toxin. Our research was aimed at defining the mechanism(s) for lanthionine toxicity. (2) The effect of lanthionine on H2S release was tested by a novel lead acetate strip test (LAST) in EA.hy926 cell cultures. Effects of glutathione, as a redox agent, were assayed. Levels of sulfane sulfur were evaluated using the SSP4 probe and flow cytometry. Protein content and glutathionylation were analyzed by Western Blotting and immunoprecipitation, respectively. Gene expression and miRNA levels were assessed by qPCR. (3) We demonstrated that, in endothelial cells, lanthionine hampers H2S release; reduces protein content and glutathionylation of transsulfuration enzyme cystathionine-β-synthase; modifies the expression of miR-200c and miR-423; lowers expression of vascular endothelial growth factor VEGF; increases Ca2+ levels. (4) Lanthionine-induced alterations in cell cultures, which involve both sulfur amino acid metabolism and calcium homeostasis, are consistent with Uremic dysfunctional characteristics and further support the Uremic Toxin role of this amino acid.

  • Zebrafish, a novel model system to study Uremic Toxins: The case for the sulfur amino acid lanthionine
    International Journal of Molecular Sciences, 2018
    Co-Authors: Alessandra F. Perna, Miriam Zacchia, Francesco Trepiccione, Evgeniya Anishchenko, Carmela Vigorito, Salvatore D’aniello, Diego Ingrosso
    Abstract:

    The non-proteinogenic amino acid lanthionine is a byproduct of hydrogen sulfide biosynthesis: the third endogenous vasodilator gas, after nitric oxide and carbon monoxide. While hydrogen sulfide is decreased in Uremic patients on hemodialysis, lanthionine is increased and has been proposed as a new Uremic Toxin, since it is able to impair hydrogen sulfide production in hepatoma cells. To characterize lanthionine as a Uremic Toxin, we explored its effects during the early development of the zebrafish (Danio rerio), a widely used model to study the organ and tissue alterations induced by xenobiotics. Lanthionine was employed at concentrations reproducing those previously detected in uremia. Light-induced visual motor response was also studied by means of the DanioVision system. Treatment of zebrafish embryos with lanthionine determined acute phenotypical alterations, on heart organogenesis (disproportion in cardiac chambers), increased heart beating, and arrhythmia. Lanthionine also induced locomotor alterations in zebrafish embryos. Some of these effects could be counteracted by glutathione. Lanthionine exerted acute effects on transsulfuration enzymes and the expression of genes involved in inflammation and metabolic regulation, and modified microRNA expression in a way comparable with some alterations detected in uremia. Lanthionine meets the criteria for classification as a Uremic Toxin. Zebrafish can be successfully used to explore Uremic Toxin effects.

  • The sulfur metabolite lanthionine: Evidence for a role as a novel Uremic Toxin
    Toxins, 2017
    Co-Authors: Alessandra F. Perna, Miriam Zacchia, Francesco Trepiccione, Diego Ingrosso
    Abstract:

    Lanthionine is a nonproteinogenic amino acid, composed of two alanine residues that are crosslinked on their β-carbon atoms by a thioether linkage. It is biosynthesized from the condensation of two cysteine molecules, while the related compound homolanthionine is formed from the condensation of two homocysteine molecules. The reactions can be carried out by either cystathionine-β-synthase (CBS) or cystathionine-γ-lyase (CSE) independently, in the alternate reactions of the transsulfuration pathway devoted to hydrogen sulfide biosynthesis. Low plasma total hydrogen sulfide levels, probably due to reduced CSE expression, are present in uremia, while homolanthionine and lanthionine accumulate in blood, the latter several fold. Uremic patients display a derangement of sulfur amino acid metabolism with a high prevalence of hyperhomocysteinemia. Uremia is associated with a high cardiovascular mortality, the causes of which are still not completely explained, but are related to Uremic toxicity, due to the accumulation of retention products. Lanthionine inhibits hydrogen sulfide production in hepatoma cells, possibly through CBS inhibition, thus providing some basis for the biochemical mechanism, which may significantly contribute to alterations of metabolism sulfur compounds in these subjects (e.g., high homocysteine and low hydrogen sulfide). We therefore suggest that lanthionine is a novel Uremic Toxin.

  • divergent behavior of hydrogen sulfide pools and of the sulfur metabolite lanthionine a novel Uremic Toxin in dialysis patients
    Biochimie, 2016
    Co-Authors: Alessandra F. Perna, Miriam Zacchia, Carmela Vigorito, Annarita Di Nunzio, Angela Amoresano, Francesca Pane, Carolina Fontanarosa, Piero Pucci, Giovanni Cirillo, Francesco Trepiccione
    Abstract:

    Abstract Dialysis patients display a high cardiovascular mortality, the causes of which are still not completely explained, but are related to Uremic toxicity. Among Uremic Toxins, homocysteine and cysteine are both substrates of cystathionine β-synthase and cystathionine γ-lyase in hydrogen sulfide biosynthesis, leading to the formation of two sulfur metabolites, lanthionine and homolanthionine, considered stable indirect biomarkers of its production. Hydrogen sulfide is involved in the modulation of multiple pathophysiological responses. In uremia, we have demonstrated low plasma total hydrogen sulfide levels, due to reduced cystathionine γ-lyase expression. Plasma hydrogen sulfide levels were measured in hemodialysis patients and healthy controls with three different techniques in comparison, allowing to discern the different pools of this gas. The protein-bound (the one thought to be the most active) and acid-labile forms are significantly decreased, while homolanthionine, but especially lanthionine, accumulate in the blood of Uremic patients. The hemodialysis regimen plays a role in determining sulfur compounds levels, and lanthionine is partially removed by a single dialysis session. Lanthionine inhibits hydrogen sulfide production in cell cultures under conditions comparable to in vivo ones. We therefore propose that lanthionine is a novel Uremic Toxin. The possible role of high lanthionine as a contributor to the genesis of hyperhomocysteinemia in uremia is discussed.

Francesco Trepiccione - One of the best experts on this subject based on the ideXlab platform.

  • Uremic Toxin Lanthionine Interferes with the Transsulfuration Pathway, Angiogenetic Signaling and Increases Intracellular Calcium.
    International journal of molecular sciences, 2019
    Co-Authors: Carmela Vigorito, Miriam Zacchia, Francesco Trepiccione, Evgeniya Anishchenko, Diego Ingrosso, Patrizia Lombari, Luigi Mele, Giovanna Capolongo, Rosanna Capasso, Alessandra F. Perna
    Abstract:

    (1) The beneficial effects of hydrogen sulfide (H2S) on the cardiovascular and nervous system have recently been re-evaluated. It has been shown that lanthionine, a side product of H2S biosynthesis, previously used as a marker for H2S production, is dramatically increased in circulation in uremia, while H2S release is impaired. Thus, lanthionine could be classified as a novel Uremic Toxin. Our research was aimed at defining the mechanism(s) for lanthionine toxicity. (2) The effect of lanthionine on H2S release was tested by a novel lead acetate strip test (LAST) in EA.hy926 cell cultures. Effects of glutathione, as a redox agent, were assayed. Levels of sulfane sulfur were evaluated using the SSP4 probe and flow cytometry. Protein content and glutathionylation were analyzed by Western Blotting and immunoprecipitation, respectively. Gene expression and miRNA levels were assessed by qPCR. (3) We demonstrated that, in endothelial cells, lanthionine hampers H2S release; reduces protein content and glutathionylation of transsulfuration enzyme cystathionine-β-synthase; modifies the expression of miR-200c and miR-423; lowers expression of vascular endothelial growth factor VEGF; increases Ca2+ levels. (4) Lanthionine-induced alterations in cell cultures, which involve both sulfur amino acid metabolism and calcium homeostasis, are consistent with Uremic dysfunctional characteristics and further support the Uremic Toxin role of this amino acid.

  • Zebrafish, a novel model system to study Uremic Toxins: The case for the sulfur amino acid lanthionine
    International Journal of Molecular Sciences, 2018
    Co-Authors: Alessandra F. Perna, Miriam Zacchia, Francesco Trepiccione, Evgeniya Anishchenko, Carmela Vigorito, Salvatore D’aniello, Diego Ingrosso
    Abstract:

    The non-proteinogenic amino acid lanthionine is a byproduct of hydrogen sulfide biosynthesis: the third endogenous vasodilator gas, after nitric oxide and carbon monoxide. While hydrogen sulfide is decreased in Uremic patients on hemodialysis, lanthionine is increased and has been proposed as a new Uremic Toxin, since it is able to impair hydrogen sulfide production in hepatoma cells. To characterize lanthionine as a Uremic Toxin, we explored its effects during the early development of the zebrafish (Danio rerio), a widely used model to study the organ and tissue alterations induced by xenobiotics. Lanthionine was employed at concentrations reproducing those previously detected in uremia. Light-induced visual motor response was also studied by means of the DanioVision system. Treatment of zebrafish embryos with lanthionine determined acute phenotypical alterations, on heart organogenesis (disproportion in cardiac chambers), increased heart beating, and arrhythmia. Lanthionine also induced locomotor alterations in zebrafish embryos. Some of these effects could be counteracted by glutathione. Lanthionine exerted acute effects on transsulfuration enzymes and the expression of genes involved in inflammation and metabolic regulation, and modified microRNA expression in a way comparable with some alterations detected in uremia. Lanthionine meets the criteria for classification as a Uremic Toxin. Zebrafish can be successfully used to explore Uremic Toxin effects.

  • The sulfur metabolite lanthionine: Evidence for a role as a novel Uremic Toxin
    Toxins, 2017
    Co-Authors: Alessandra F. Perna, Miriam Zacchia, Francesco Trepiccione, Diego Ingrosso
    Abstract:

    Lanthionine is a nonproteinogenic amino acid, composed of two alanine residues that are crosslinked on their β-carbon atoms by a thioether linkage. It is biosynthesized from the condensation of two cysteine molecules, while the related compound homolanthionine is formed from the condensation of two homocysteine molecules. The reactions can be carried out by either cystathionine-β-synthase (CBS) or cystathionine-γ-lyase (CSE) independently, in the alternate reactions of the transsulfuration pathway devoted to hydrogen sulfide biosynthesis. Low plasma total hydrogen sulfide levels, probably due to reduced CSE expression, are present in uremia, while homolanthionine and lanthionine accumulate in blood, the latter several fold. Uremic patients display a derangement of sulfur amino acid metabolism with a high prevalence of hyperhomocysteinemia. Uremia is associated with a high cardiovascular mortality, the causes of which are still not completely explained, but are related to Uremic toxicity, due to the accumulation of retention products. Lanthionine inhibits hydrogen sulfide production in hepatoma cells, possibly through CBS inhibition, thus providing some basis for the biochemical mechanism, which may significantly contribute to alterations of metabolism sulfur compounds in these subjects (e.g., high homocysteine and low hydrogen sulfide). We therefore suggest that lanthionine is a novel Uremic Toxin.

  • divergent behavior of hydrogen sulfide pools and of the sulfur metabolite lanthionine a novel Uremic Toxin in dialysis patients
    Biochimie, 2016
    Co-Authors: Alessandra F. Perna, Miriam Zacchia, Carmela Vigorito, Annarita Di Nunzio, Angela Amoresano, Francesca Pane, Carolina Fontanarosa, Piero Pucci, Giovanni Cirillo, Francesco Trepiccione
    Abstract:

    Abstract Dialysis patients display a high cardiovascular mortality, the causes of which are still not completely explained, but are related to Uremic toxicity. Among Uremic Toxins, homocysteine and cysteine are both substrates of cystathionine β-synthase and cystathionine γ-lyase in hydrogen sulfide biosynthesis, leading to the formation of two sulfur metabolites, lanthionine and homolanthionine, considered stable indirect biomarkers of its production. Hydrogen sulfide is involved in the modulation of multiple pathophysiological responses. In uremia, we have demonstrated low plasma total hydrogen sulfide levels, due to reduced cystathionine γ-lyase expression. Plasma hydrogen sulfide levels were measured in hemodialysis patients and healthy controls with three different techniques in comparison, allowing to discern the different pools of this gas. The protein-bound (the one thought to be the most active) and acid-labile forms are significantly decreased, while homolanthionine, but especially lanthionine, accumulate in the blood of Uremic patients. The hemodialysis regimen plays a role in determining sulfur compounds levels, and lanthionine is partially removed by a single dialysis session. Lanthionine inhibits hydrogen sulfide production in cell cultures under conditions comparable to in vivo ones. We therefore propose that lanthionine is a novel Uremic Toxin. The possible role of high lanthionine as a contributor to the genesis of hyperhomocysteinemia in uremia is discussed.

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