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Hyperhomocysteinemia in uremia--a red flag in a disrupted circuit.

Abstract：

: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.

journal_name

Semin Dial

journal_title

Seminars in dialysis

authors

Perna AF,Ingrosso D,Violetti E,Luciano MG,Sepe I,Lanza D,Capasso R,Ascione E,Raiola I,Lombardi C,Stenvinkel P,Massy Z,De Santo NG

doi

10.1111/j.1525-139X.2009.00579.x

subject

Has Abstract

pub_date

2009-07-01 00:00:00

pages

351-6

issue

eissn

0894-0959

issn

1525-139X

pii

SDI579

journal_volume

pub_type

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Hyperhomocysteinemia in uremia--a red flag in a disrupted circuit.