Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.
Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China.
FASEB J. 2020 Sep;34(9):11474-11487. doi: 10.1096/fj.201902957RR. Epub 2020 Jul 30.
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 Fe 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.
缺氧是慢性肾脏病（CKD）的一个关键发病特征。Klotho 具有肾脏保护作用，其在 CKD 患者中的表达通常受到抑制。我们发现单侧输尿管梗阻模型小鼠的慢性缺氧与肾脏 Klotho 启动子甲基化和表达沉默有关。低剂量的硫氢化钠（NaHS）通过去甲基化 Klotho 启动子并恢复其表达，有效地改善了小鼠模型的肾小管间质纤维化。在机制上，CKD 的低氧微环境降低了细胞的氧可用性和铁浓度，导致十号十一号转位酶（TET）的活性受损，而 TET 在维持 Klotho 启动子去甲基化状态中至关重要。NaHS 治疗极大地改善了缺氧状态，恢复了 TET 活性，逆转了 DNA 甲基化，从而增加了 Klotho 的表达。我们的研究结果强烈表明，纠正缺氧状态以恢复 TET 活性可能是治疗 CKD 的一种有前途的治疗策略。
