Epigenetics in hyperhomocysteinemic states. A special focus on uremia.
Aim of this article is to review the topic of epigenetic control of gene expression, especially regarding DNA methylation, in chronic kidney disease and uremia. Hyperhomocysteinemia is considered an independent cardiovascular risk factor, although the most recent intervention studies utilizing folic acid are negative. The accumulation of homocysteine in blood leads to an intracellular increase of S-adenosylhomocysteine (AdoHcy), a powerful competitive methyltransferase inhibitor, which is itself considered a predictor of cardiovascular events. The extent of methylation inhibition of each individual methyltransferase depends on the methyl donor S-adenosylmethionine (AdoMet) availability, on the [AdoMet]/[AdoHcy] ratio, and on the individual Km value for AdoMet and Ki for AdoHcy. DNA methyltransferases are among the principal targets of hyperhomocysteinemia, as studies in several cell culture and animal models, as well as in humans, almost unequivocally show. In vivo, DNA methylation may be also influenced by various factors in different tissues, for example by rate of cell growth, folate status, etc. and importantly inflammation. In chronic kidney disease and in uremia, hyperhomocysteinemia is commonly seen, and can be associated with global DNA hypomethylation, and with abnormal allelic expression of genes regulated through methylation. This alteration is susceptible of reversal upon homocysteine-lowering therapy obtained through folate administration. If this abnormality will translate itself in alterations of expression of genes relevant to the pathogenesis of this disease still remains to be established. In addition, these results establish a link between the epigenetic control of gene expression and xenobiotic influences, such as folate therapy.
Ingrosso
Diego
D
Department of Biochemistry and Biophysics "F. Cedrangolo", Second University of Naples, Italy. diego.ingrosso@unina2.it
Perna
Alessandra F
AF
D050197:Atherosclerosis / Q000235:genetics; D002986:Clinical Trials as Topic; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005492:Folic Acid / Q000627:therapeutic use; D006801:Humans; D020138:Hyperhomocysteinemia / Q000188:drug therapy / Q000235:genetics*; D012435:S-Adenosylhomocysteine / Q000097:blood; D014511:Uremia / Q000235:genetics* / Q000378:metabolism
D005492:Folic Acid; D012435:S-Adenosylhomocysteine