Indoxyl Sulfate Enhance the Hypermethylation of Klotho and Promote the Process of Vascular Calcification in Chronic Kidney Disease.
Indoxyl Sulfate Enhance the Hypermethylation of Klotho and Promote the Process of Vascular Calcification in Chronic Kidney Disease.
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DOI：
10.7150/ijbs.15195
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发表时间：
2016
影响因子：
9.2
通讯作者：
Ding X
中科院分区：
文献类型：
--
作者：
Chen J;Zhang X;Zhang H;Liu T;Zhang H;Teng J;Ji J;Ding X
慢性肾脏病（CKD）是Klotho缺乏症的一种状态。Klotho的表达可能因癌细胞中DNA高甲基化而受到抑制，因此我们研究了Klotho在人主动脉平滑肌细胞（HASMC）中表达调节的作用和可能的机制。本文报道终末期肾病患者桡动脉血管Klotho甲基化。体外培养的HASMCs和5/6肾切除的Sprague道利（SD）大鼠分别用硫酸吲哚酚（IS）处理作为体外和体内模型。IS增加了HASMCs中Klotho基因的CpG超甲基化，降低了Klotho的表达，并增强了HASMCs的钙化。DNA甲基转移酶（DNMT）1和3a在IS处理的HASMCs中的表达显著增加，并且5-氮杂-2 '-脱氧胞苷（5Aza-2dc）特异性抑制DNA甲基转移酶1引起Klotho基因的去甲基化并增加Klotho表达。在大鼠中，注射IS可增强血管钙化，增加Klotho基因的CpG超甲基化，并降低主动脉中层中Klotho的表达，所有这些变化均可通过5Aza-2dc治疗逆转。IS对血管Klotho基因表达的转录抑制和对Klotho的表观遗传修饰可能是CKD血管钙化的重要病理机制。
Chronic kidney disease (CKD) is a state of Klotho deficiency. The Klotho expression may be suppressed due to DNA hypermethylation in cancer cells so we have investigated the effects and possible mechanisms by which Klotho expression is regulated in human aortic smooth muscle cells (HASMCs). The vascular Klotho hypermethylation in radial arteries of patients with end-stage renal disease was described. Cultured HASMCs and 5/6-nephrectomized Sprague Dawley (SD) rats treated with indoxyl sulfate (IS) were used as in vitro and in vivo models, respectively. IS increased CpG hypermethylation of the Klotho gene and decreased Klotho expression in HASMCs, and potentiated HASMCs calcification. The expression of DNA methyltransferase (DNMT) 1 and 3a in HASMCs treated with IS was significantly increased and specific inhibition of DNA methyltransferase 1 by 5-aza-2'-deoxycytidine(5Aza-2dc) caused demethylation of the Klotho gene and increased Klotho expression. In rats, injection of IS potentiated vascular calcification, increased CpG hypermethylation of the Klotho gene and decreased Klotho expression in the aortic medial layer and all of these changes could be reverted by 5Aza-2dc treatment. Transcriptional suppression of vascular Klotho gene expression by IS and epigenetic modification of Klotho by IS may be an important pathological mechanism of vascular calcification in CKD.
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αKlotho 和血管钙化：一个不断发展的范例。
DOI：
10.1097/01.mnh.0000447024.97464.a3
发表时间：
2014-07
影响因子：
3.2
作者：
Hu MC;Kuro-o M;Moe OW
通讯作者：
Moe OW
影响因子：
6.1
作者：
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通讯作者：
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影响因子：
4.3
作者：
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通讯作者：
Vanholder, Raymond
影响因子：
4.2
作者：
Liabeuf S;Drüeke TB;Massy ZA
通讯作者：
Massy ZA
影响因子：
6.2
作者：
Montes de Oca, Addy;Madueno, Juan A.;Aguilera-Tejero, Escolastico
通讯作者：
Aguilera-Tejero, Escolastico