METTL3-mediated m(6)A modification of TIMP2 mRNA promotes podocyte injury in diabetic nephropathy.
METTL3-mediated m(6)A modification of TIMP2 mRNA promotes podocyte injury in diabetic nephropathy.
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METTL3 介导的 TIMP2 mRNA 的 m(6)A 修饰促进糖尿病肾病足细胞损伤。
DOI：
10.1016/j.ymthe.2022.01.002
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发表时间：
2022-04-06
影响因子：
12.4
通讯作者：
Wu, Yonggui
中科院分区：
文献类型：
--
作者：
Jiang, Ling;Liu, Xueqi;Hu, Xueru;Gao, Li;Zeng, Hanxu;Wang, Xian;Huang, Yuebo;Zhu, Wei;Wang, Jianan;Wen, Jiagen;Meng, Xiaoming;Wu, Yonggui
表观遗传学改变存在于许多生理和病理过程中。N6-甲基腺苷(M6A)修饰是真核基因中最常见的修饰。然而，M6A修饰在糖尿病肾病(DN)中的作用仍不清楚。在这里，我们发现M6A修饰在1型和2型糖尿病小鼠的肾脏中显著上调，这是由METTL3水平升高引起的。此外，糖尿病肾病患者肾活检组织中足细胞中METTL3水平升高，与肾脏损害有关。METTL3基因敲除可显著降低高糖刺激的足细胞炎症和细胞凋亡，而其过表达在体外可显著加重这些反应。足细胞条件性基因敲除METTL3显著减轻链脲佐菌素(STZ)诱导的糖尿病小鼠足细胞损伤和蛋白尿。在治疗方面，在体内用腺相关病毒血清型9(AAV9)-shMETTL3沉默METTL3可以减轻STZ诱导的糖尿病小鼠和db/db小鼠的蛋白尿和组织病理学损伤。在机制上，METTL3通过胰岛素样生长因子2mRNA结合蛋白2(IGF2BP2)依赖的M6A修饰TIMP2来调节Notch信号，并发挥促炎和促凋亡作用。综上所述，本研究提示METTL3介导的M6A修饰是糖尿病肾病足细胞损伤的重要机制。通过编写器酶METTL3靶向m6A是治疗糖尿病肾病的一种潜在方法。Wu和他的同事们首次揭示了METTL3介导的M6A修饰是糖尿病肾病足细胞损伤的重要机制。通过编写器酶METTL3靶向m6A是治疗糖尿病肾病的一种潜在方法。
Epigenetic changes are present in many physiological and pathological processes. The N6-methyladenosine (m6A) modification is the most common modification in eukaryotic mRNA. However, the role of m6A modification in diabetic nephropathy (DN) remains elusive. Here, we found that m6A modification was significantly upregulated in the kidney of type 1 and type 2 diabetic mice, which was caused by elevated levels of METTL3. Moreover, METTL3 is increased in podocyte of renal biopsy from patients with DN, which is related to renal damage. METTL3 knockout significantly reduced the inflammation and apoptosis in high glucose (HG)-stimulated podocytes, while its overexpression significantly aggravated these responses in vitro. Podocyte-conditional knockout METTL3 significantly alleviated podocyte injury and albuminuria in streptozotocin (STZ)-induced diabetic mice. Therapeutically, silencing METTL3 with adeno-associated virus serotype-9 (AAV9)-shMETTL3 in vivo mitigated albuminuria and histopathological injury in STZ-induced diabetic mice and db/db mice. Mechanistically, METTL3 modulated Notch signaling via the m6A modification of TIMP2 in an insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2)-dependent manner and exerted pro-inflammatory and pro-apoptotic effects. In summary, this study suggested that METTL3-mediated m6A modification is an important mechanism of podocyte injury in DN. Targeting m6A through the writer enzyme METTL3 is a potential approach for the treatment of DN. Wu and his colleagues reveal for the first time that METTL3-mediated m6A modification is an important mechanism of podocyte injury in DN. Targeting m6A through the writer enzyme METTL3 is a potential approach for the treatment of DN.
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影响因子：
20.8
作者：
De Jesus, Dario F.;Zhang, Zijie;Kulkarni, Rohit N.
通讯作者：
Kulkarni, Rohit N.
Sirt6 缺陷通过靶向 Notch 信号传导加剧足细胞损伤和蛋白尿。
影响因子：
16.6
作者：
Liu M;Liang K;Zhen J;Zhou M;Wang X;Wang Z;Wei X;Zhang Y;Sun Y;Zhou Z;Su H;Zhang C;Li N;Gao C;Peng J;Yi F
通讯作者：
Yi F
影响因子：
4.8
作者：
Chernov, Andrei V.;Sounni, Nor Eddine;Strongin, Alex Y.
通讯作者：
Strongin, Alex Y.
DOI：
10.1016/j.bbrc.2019.05.168
发表时间：
2019-08-13
影响因子：
3.1
作者：
Liu, Qingbai;Li, Meng;Fu, Bin
通讯作者：
Fu, Bin
影响因子：
13.6
作者：
Johnson, Ali C. M.;Zager, Richard A.
通讯作者：
Zager, Richard A.