Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China.
Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, People's Republic of China.
Clin Epigenetics. 2020 Jul 2;12(1):98. doi: 10.1186/s13148-020-00892-8.
Ten-eleven translocation (Tet) methyl-cytosine dioxygenases (including Tet1/2/3)-mediated 5mC oxidation and DNA demethylation play important roles in embryonic development and adult tissue homeostasis. The expression of Tet2 and Tet3 genes are relatively abundant in the adult murine kidneys while Tet1 gene is expressed at a low level. Although Tet3 has been shown to suppress kidney fibrosis, the role of Tet2 in kidney physiology as well as renal ischemia-reperfusion (IR) injury is still largely unknown.
Tet2 mice displayed normal kidney morphology and renal function as WT mice while the expression of genes associated with tight junction and adherens junction was impaired. At 24 h post-renal IR, Tet2 mice showed higher SCr and BUN levels, more severe tubular damage, and elevated expression of Kim1 and Ngal genes in the kidney in comparison with WT mice. Moreover, the transcriptomic analysis revealed augmented inflammatory response in the kidneys of Tet2 mice.
Tet2 is dispensable for kidney development and function at baseline condition while protects against renal IR injury possibly through repressing inflammatory response. Our findings suggest that Tet2 may be a potential target for the intervention of IR-induced acute kidney injury (AKI).
十-十一易位（Tet）甲基胞嘧啶双加氧酶（包括 Tet1/2/3）介导的 5mC 氧化和 DNA 去甲基化在胚胎发育和成人组织稳态中发挥重要作用。在成年小鼠肾脏中，Tet2 和 Tet3 基因的表达相对丰富，而 Tet1 基因的表达水平较低。尽管已经表明 Tet3 可抑制肾纤维化，但 Tet2 在肾脏生理学以及肾缺血再灌注（IR）损伤中的作用仍知之甚少。
与 WT 小鼠相比，Tet2 小鼠的肾脏形态和肾功能正常，而紧密连接和黏着连接相关基因的表达受到损害。在肾 IR 后 24 小时，与 WT 小鼠相比，Tet2 小鼠的血清肌酐（SCr）和血尿素氮（BUN）水平更高，肾小管损伤更严重，肾脏中 Kim1 和 Ngal 基因的表达水平升高。此外，转录组分析显示 Tet2 小鼠肾脏中的炎症反应增强。
Tet2 在基础条件下对肾脏发育和功能不是必需的，但可通过抑制炎症反应来保护肾脏免受 IR 损伤。我们的研究结果表明，Tet2 可能是干预 IR 诱导的急性肾损伤（AKI）的潜在靶点。
