Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Suppression of Klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase expression and DNA hypermethylation. 2223 53

Epigenetic regulation plays a major role in uremic toxin-induced chronic kidney disease (CKD) progression. The KLOTHO protein is a key modulator of homeostasis in renal function. Uremic toxin accumulation can induce DNA methyltransferase (DNMT) protein expression, which is involved in the silencing of KLOTHO through hypermethylation. Treatment with DNMT inhibitors can induce a hypermethylated status of KLOTHO and suppress mRNA and protein expression. Epigenetic targeting of specific genes may become an effective strategy to prevent progression of uremia-related CKD.
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PMID:KLOTHO methylation is linked to uremic toxins and chronic kidney disease. 2063 79

Vascular calcification is one of the most important factors for cardiovascular and all-cause mortality in patients with end-stage renal diseases (ESRD). The current study was aimed to investigate the function and mechanisms of miR-34b on the calcification of vascular smooth muscle cells (VSMCs) both in vitro and in vivo. We found that the expression of miR-34b was significantly suppressed in VSMCs with high inorganic phosphate (Pi) treatment, as well as mouse arteries derived from 5/6 nephrectomy with a high-phosphate diet (0.9% Pi, 5/6 NTP) and human renal arteries from uraemia patients. Overexpression of miR-34b alleviated calcification of VSMCs, while VSMCs calcification was enhanced by inhibiting the expression of miR-34b. Bisulphite sequencing PCR (BSP) uncovered that CpG sites upstream of miR-34b DNA were hypermethylated in calcified VSMCs and calcified arteries due to 5/6 NTP, as well as calcified renal arterial tissues from uraemia patients. Meantime, increased DNA methyltransferase 3a (DNMT3a) resulted in the hypermethylation of miR-34b in VSMCs, while 5-aza-2'-deoxycytidine (5-aza) reduced the methylation rate of miR-34b and restored the expression of miR-34b in VSMCs. When DNMT3a was knocked down using DNMT3a siRNA, the effect of 3.5 mM of Pi on calcification of VSMCs was abrogated. In addition, Notch1 was validated as the functional target of miR-34b and involved in the process of calcification of VSMCs. Taken together, our data showed a specific role for miR-34b in regulating calcification of VSMCs both in vitro and in vivo, which was regulated by upstream DNA methylation of miR-34b and modulated by the downstream target gene expression, Notch1. These results suggested that modulation of miR-34b may offer new insight into a novel therapeutic approach for vascular calcification.
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PMID:Aberration methylation of miR-34b was involved in regulating vascular calcification by targeting Notch1. 3112 59