The kidney is the major site of S-adenosylhomocysteine disposal in humans

Garibotto, Giacomo; Valli, Alessandro; Anderstam, Björn; Eriksson, Monica; Suliman, Mohamed E.; Balbi, Manrico; Rollando, Daniela; Vigo, Emanuela; Lindholm, Bengt

doi:10.1038/ki.2009.117

Cited by 52 publications

(38 citation statements)

References 25 publications

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“…44 Furthermore, in patients with CKD, SAH accumulates more compared with homocysteine because the kidneys are the major site of SAH disposal in humans. 45 In accordance, in this study, we observed higher differences in SAH levels (30.9-fold increase in patients on dialysis) than in homocysteine levels (2.4-fold) and SAM levels (4.8-fold).…”

Section: 41supporting

confidence: 78%

SuperTAG Methylation-specific Digital Karyotyping Reveals Uremia-induced Epigenetic Dysregulation of Atherosclerosis-Related Genes

Zawada

Rogačev

Hummel

et al. 2012

Circ Cardiovasc Genet

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Background— Accelerated atherosclerosis is a hallmark of chronic kidney disease (CKD). Although the role of epigenetic dysregulation in atherosclerosis is increasingly appreciated, only a few studies focused on epigenetics in CKD-associated cardiovascular disease, virtually all of which assessed epigenetic dysregulation globally. We hypothesized that gene-specific epigenetic dysregulation in CKD exists, affecting genes pertinent to inflammation and atherosclerosis. Methods and Results— Ten clinically stable patients undergoing hemodialysis therapy and 10 healthy age- and sex-matched controls were recruited. Genome-wide analysis of DNA methylation was performed by SuperTAG methylation-specific digital karyotyping, in order to identify genes differentially methylated in CKD. Analysis of 27 043 436 tags revealed 4288 genomic loci with differential DNA methylation ( P <10 –10 ) between hemodialysis patients and control subjects. Annotation of UniTags to promoter databases allowed us to identify 52 candidate genes associated with cardiovascular disease and 97 candidate genes associated with immune/infection diseases. These candidate genes could be classified to distinct proatherogenic processes, including lipid metabolism and transport (eg, HMGCR , SREBF1 , LRP5 , EPHX2 , and FDPS ), cell proliferation and cell-cycle regulation (eg, MIK67 , TP53 , and ALOX12 ), angiogenesis (eg, ANGPT2 , ADAMTS10 , and FLT4 ), and inflammation (eg, TNFSF10 , LY96 , IFNGR1 , HSPA1A , and IL12RB1 ). Conclusions— We provide a comprehensive analysis of genome-wide epigenetic alterations in CKD, identifying candidate genes associated with proatherogenic and inflammatory processes. These results may spur further research in the field of epigenetics in kidney disease and point to new therapeutic strategies in CKD-associated atherosclerotic disease.

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Section: 41supporting

confidence: 78%

SuperTAG Methylation-specific Digital Karyotyping Reveals Uremia-induced Epigenetic Dysregulation of Atherosclerosis-Related Genes

Zawada

Rogačev

Hummel

et al. 2012

Circ Cardiovasc Genet

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“…259 260 A significant amount of homocysteine metabolism occurs in the kidney [47] and this tissue has 261 been shown to be a major factor under other conditions, such as diabetes, that are characterized 262 by aberrant homocysteine balance [30]. Although the expression of BHMT in the rodent kidney 263 is quite low [48], we found that exercise resulted in a significant increase in renal BHMT activity 264 in the control diet group, as well as the folate-restricted group. It is not clear whether these 265 alterations in renal BHMT activity are biologically sufficient to explain the prevention of 266 hyperhomocysteinemia by exercise.…”

mentioning

confidence: 76%

Exercise prevents hyperhomocysteinemia in a dietary folate-restricted mouse model

Neuman¹,

Albright²,

Schalinske³

2013

Nutrition Research

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Hyperhomocysteinemia is a condition that results from altered methyl group metabolism and is associated with numerous pathological conditions. A number of nutritional and hormonal factors have been shown to influence circulating homocysteine concentrations; however, the impact of exercise on homocysteine and methyl group balance is not well understood. Our hypothesis was that exercise represents an effective means to prevent hyperhomocysteinemia in a folate-independent manner. The purpose of this study was to determine the influence of exercise on homocysteine metabolism in a dietary folate-restricted mouse model characterized by moderate hyperhomocysteinemia. Female outbred mice (12 weeks old) were assigned to either a sedentary or free-access wheel exercise group. Following a 4-week acclimation period, half of the mice in each group were provided a folate-restricted diet for 7-weeks prior to euthanasia and tissue collection. As expected, folate-restricted sedentary mice exhibited a 2-fold increase in plasma total homocysteine concentrations; however, exercise completely prevented the increase in circulating homocysteine concentrations. Moreover, exercise reduced plasma homocysteine concentrations 36% within the group fed only the control diet. The prevention of hyperhomocysteinemia by exercise appears, at least in part, to be the result of increased folate-independent homocysteine remethylation owing to a 2-fold increase in renal betaine homocysteine S-methyltransferase. To our knowledge, this is the first report demonstrating the prevention of hyperhomocysteinemia by exercise in a dietary folate-restriction model. Future research will be directed at determining if exercise can have a positive impact on other nutritional, hormonal, and genetic models of hyperhomocysteinemia relevant to humans. Hyperhomocysteinemia is a condition that results from altered methyl group metabolism and is 30 associated with numerous pathological conditions. A number of nutritional and hormonal factors 31 have been shown to influence circulating homocysteine concentrations; however, the impact of 32 exercise on homocysteine and methyl group balance is not well understood. Our hypothesis was 33 that exercise represents an effective means to prevent hyperhomocysteinemia in a folate-34 independent manner. The purpose of this study was to determine the influence of exercise on 35 homocysteine metabolism in a dietary folate-restricted mouse model characterized by moderate 36 hyperhomocysteinemia. Female outbred mice (12 wk old) were assigned to either a sedentary or 37 free-access wheel exercise group. Following a 4-wk acclimation period, half of the mice in each 38 group were provided a folate-restricted diet for 7-wk prior to euthanasia and tissue collection. As 39 expected, folate-restricted sedentary mice exhibited a 2-fold increase in plasma total 40 homocysteine concentrations; however, exercise completely prevented the increase in circulating 41 homocysteine concentrations. Moreover, exercise reduced plasma homocysteine c...

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“…Since most cells lack transsulfuration enzymes, excess SAH and homocysteine produced as a consequence of normal methylation processes are transported to liver and kidneys for catabolism (122). Circulating homocysteine concentrations reflect the efficacy of catabolism in the liver and kidneys (123)(124)(125).…”

Section: Hepatic and Renal Functionmentioning

confidence: 99%

“…The kidney is the major site of SAH disposal (122), and renal tubules avidly reabsorb homocysteine (134). Hence, normal kidney function comprises handling most of the homocysteine produced in the body.…”

Section: Hepatic and Renal Functionmentioning

confidence: 99%

Effect of Nitrous Oxide Exposure During Surgery on the Homocysteine Concentrations of Children

Pichardo¹,

Luginbuehl²,

Shakur³

et al. 2013

Survey of Anesthesiology

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In this study we determined the effect of nitrous oxide (N 2 O) on homocysteine concentrations in children and whether blood levels of folate, vitamin B12, B6, methylmalonic acid (MMA) and methylenetetrahydrofolate reductase C6777T genotype affected this relationship. Homocysteine was measured before and after N 2 O. Vitamin levels, MMA and genotype were determined preoperatively. Median age of the 32 participants was 11 months (3-126 months). All children had folate and B6 levels above deficiency values (7.4, 20nmol/L respectively). Five children had MMA levels indicating deficiency (≥0.21µmol/L). Postexposure homocysteine concentrations increased by 25% (P= <0.001). Duration of exposure and initial homocysteine concentrations were predictors of the increase (r 2 = 0.821, P= <0.001).Vitamin B12 and initial homocysteine concentrations were inversely associated (r 2 = 0.277, P= 0.004). Folate, vitamin B6 and genotype showed no effect. In conclusion, N 2 O exposure leads to increased homocysteine in children. Studies investigating benefit of pre-surgical vitamin B12 supplementation may prove worthwhile.iii ACKNOWLEDGMENTS

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The kidney is the major site of S-adenosylhomocysteine disposal in humans

Cited by 52 publications

References 25 publications

SuperTAG Methylation-specific Digital Karyotyping Reveals Uremia-induced Epigenetic Dysregulation of Atherosclerosis-Related Genes

SuperTAG Methylation-specific Digital Karyotyping Reveals Uremia-induced Epigenetic Dysregulation of Atherosclerosis-Related Genes

Exercise prevents hyperhomocysteinemia in a dietary folate-restricted mouse model

Effect of Nitrous Oxide Exposure During Surgery on the Homocysteine Concentrations of Children

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