Suppression of Klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase expression and DNA hypermethylation
Resource
KIDNEY INTERNATIONAL, 81(7), 640-650
Journal
Kidney International
Journal Volume
81
Journal Issue
7
Pages
640-650
Date Issued
2012
Date
2012
Author(s)
Abstract
The expression of the renoprotective antiaging gene Klotho is decreased in uremia. Recent studies suggest that Klotho may be a tumor suppressor, and its expression may be repressed by DNA hypermethylation in cancer cells. Here we investigated the effects and possible mechanisms by which Klotho expression is regulated during uremia in uninephrectomized B-6 mice given the uremic toxins indoxyl sulfate or p-cresyl sulfate. Cultured human renal tubular HK2 cells treated with these toxins were used as an in vitro model. Injections of indoxyl sulfate or p-cresyl sulfate increased their serum concentrations, kidney fibrosis, CpG hypermethylation of the Klotho gene, and decreased Klotho expression in renal tubules of these mice. The expression of DNA methyltransferases 1, 3a, and 3b isoforms in HK2 cells treated with indoxyl sulfate or p-cresyl sulfate was significantly increased. Specific inhibition of DNA methyltransferase isoform 1 by 5-aza-2′-deoxycytidine caused demethylation of the Klotho gene and increased Klotho expression in vitro. Thus, inhibition of Klotho gene expression by uremic toxins correlates with gene hypermethylation, suggesting that epigenetic modification of specific genes by uremic toxins may be an important pathological mechanism of disease. ? 2012 International Society of Nephrology.
Subjects
DNA methylation; DNA methyltransferase; Klotho; uremic toxin
SDGs
Other Subjects
5 aza 2' deoxycytidine; creatinine; DNA methyltransferase; DNA methyltransferase 1; DNA methyltransferase 3A; DNA methyltransferase 3B; glutathione transferase alpha; Klotho protein; messenger RNA; nitrogen; urea; uremic toxin; animal experiment; animal model; animal tissue; article; body weight; controlled study; CpG island; creatinine blood level; DNA methylation; DNA modification; down regulation; gene; gene expression regulation; gene overexpression; human; human cell; in vitro study; in vivo study; kidney fibrosis; klotho gene; mouse; nonhuman; priority journal; protein expression; protein localization; real time polymerase chain reaction; urea nitrogen blood level; uremia; Western blotting; Animals; Azacitidine; Cell Line; CpG Islands; Cresols; DNA (Cytosine-5-)-Methyltransferase; DNA Methylation; Gene Expression; Glucuronidase; Humans; Indican; Kidney; Mice; Protein Binding; Toxins, Biological; Uremia
Type
journal article
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