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Hydrogen sulfide attenuates renal fibrosis by inducing TET‐dependent DNA demethylation on Klotho promoter
The FASEB Journal ( IF 4.8 ) Pub Date : 2020-07-30 , DOI: 10.1096/fj.201902957rr Yulu Gu 1, 2 , Jing Chen 1, 3 , Han Zhang 1, 3 , Ziyan Shen 1, 3 , Hong Liu 1, 3 , Shiqi Lv 1, 2 , Xixi Yu 1, 2 , Di Zhang 1, 2 , Xiaoqiang Ding 1, 2, 3, 4 , Xiaoyan Zhang 1, 2, 3, 4
The FASEB Journal ( IF 4.8 ) Pub Date : 2020-07-30 , DOI: 10.1096/fj.201902957rr Yulu Gu 1, 2 , Jing Chen 1, 3 , Han Zhang 1, 3 , Ziyan Shen 1, 3 , Hong Liu 1, 3 , Shiqi Lv 1, 2 , Xixi Yu 1, 2 , Di Zhang 1, 2 , Xiaoqiang Ding 1, 2, 3, 4 , Xiaoyan Zhang 1, 2, 3, 4
Affiliation
Hypoxia is a key pathogenetic characteristic of chronic kidney disease (CKD). Klotho has renoprotective effect and its expression is commonly suppressed in CKD patients. We showed that chronic hypoxia in unilateral ureteral obstruction model mice is associated with renal Klotho promoter methylation and expression silencing. Administration of low‐dose of sodium hydrosulfide (NaHS) effectively ameliorated renal tubulointerstitial fibrosis in the mouse model by demethylating Klotho promoter and restoring its expression. Mechanistically, hypoxia microenvironment in CKD reduced cellular oxygen availability and Fe2+ concentration, and led to impaired activity of ten‐eleven translocation (TET), which is critical in maintaining Klotho promoter demethylation status. NaHS treatment greatly improved hypoxia condition, restored TET activity, reversed DNA methylation, and thus, increased Klotho expression. Our results strongly suggested that correcting hypoxia condition to restore TET activity could be a promising therapeutic strategy against CKD.
中文翻译:
硫化氢通过诱导 Klotho 启动子上 TET 依赖性 DNA 去甲基化来减轻肾纤维化
缺氧是慢性肾脏病 (CKD) 的关键发病特征。Klotho 具有肾脏保护作用,其表达通常在 CKD 患者中受到抑制。我们发现单侧输尿管梗阻模型小鼠的慢性缺氧与肾 Klotho 启动子甲基化和表达沉默有关。通过去甲基化 Klotho 启动子并恢复其表达,低剂量硫氢化钠 (NaHS) 的给药可有效改善小鼠模型中的肾小管间质纤维化。从机制上讲,CKD 中的缺氧微环境降低了细胞氧的可用性和 Fe2+ 浓度,并导致 10-11 易位 (TET) 活性受损,这对于维持 Klotho 启动子去甲基化状态至关重要。NaHS 治疗大大改善了缺氧状况,恢复了 TET 活性,逆转 DNA 甲基化,从而增加 Klotho 表达。我们的结果强烈表明,纠正缺氧状况以恢复 TET 活性可能是一种有前途的 CKD 治疗策略。
更新日期:2020-07-30
中文翻译:
硫化氢通过诱导 Klotho 启动子上 TET 依赖性 DNA 去甲基化来减轻肾纤维化
缺氧是慢性肾脏病 (CKD) 的关键发病特征。Klotho 具有肾脏保护作用,其表达通常在 CKD 患者中受到抑制。我们发现单侧输尿管梗阻模型小鼠的慢性缺氧与肾 Klotho 启动子甲基化和表达沉默有关。通过去甲基化 Klotho 启动子并恢复其表达,低剂量硫氢化钠 (NaHS) 的给药可有效改善小鼠模型中的肾小管间质纤维化。从机制上讲,CKD 中的缺氧微环境降低了细胞氧的可用性和 Fe2+ 浓度,并导致 10-11 易位 (TET) 活性受损,这对于维持 Klotho 启动子去甲基化状态至关重要。NaHS 治疗大大改善了缺氧状况,恢复了 TET 活性,逆转 DNA 甲基化,从而增加 Klotho 表达。我们的结果强烈表明,纠正缺氧状况以恢复 TET 活性可能是一种有前途的 CKD 治疗策略。