MBD2 Mediates Septic AKI through Activation of PKCη/p38MAPK and the ERK1/2 Axis.
MBD2 Mediates Septic AKI through Activation of PKCη/p38MAPK and the ERK1/2 Axis.
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MBD2 通过激活 PKCγ/p38MAPK 和 ERK1/2 轴介导脓毒性 AKI
DOI：
10.1016/j.omtn.2020.09.028
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发表时间：
2021-03-05
期刊：
影响因子：
--
通讯作者：
Zhang D
中科院分区：
文献类型：
--
作者：
Xie Y;Liu B;Pan J;Liu J;Li X;Li H;Qiu S;Xiang X;Zheng P;Chen J;Yuan Y;Dong Z;Zhang D
我们之前的研究表明，甲基-CpG 结合域蛋白 2 (MBD2) 介导万古霉素 (VAN) 诱导的急性肾损伤 (AKI)。然而，MBD2 在脓毒症 AKI 中的作用和调节尚不清楚。在此，MBD2 是由波士顿大学小鼠近曲小管 (BUMPT) 和小鼠中的脂多糖 (LPS) 诱导的。对于体外和体内实验，我们表明，通过 MBD2 小干扰 RNA (siRNA) 和 MBD2 敲除 (KO) 抑制 MBD2 可显着提高存活率，并减弱 LPS 和盲肠结扎穿刺 (CLP) 诱导的 AKI、肾细胞凋亡和炎症因子产生。整体基因表达分析和体外实验表明，LPS 引起的蛋白激酶 C eta (PKCη) 的表达在 MBD2-KO 小鼠和 MBD2 siRNA 中分别受到显着抑制。从机制上讲，染色质免疫沉淀 (ChIP) 分析表明 MBD2 通过抑制启动子甲基化直接结合 PKCη 的启动子区域 CpG 岛。此外，PKCn siRNA 通过灭活 p38 丝裂原激活蛋白激酶 (MAPK) 和细胞外信号调节激酶 (ERK)1/2 来提高存活率并减弱 LPS 诱导的 BUMPT 细胞凋亡和炎症因子产生，这在 CLP 诱导的 AKI 中通过 PKCn siRNA 治疗进一步得到验证。最后，MBD2-KO 小鼠通过 PKCη/p38MAPK 和 ERK1/2 信号传导的失活表现出 CLP 诱导的肾细胞凋亡和炎症因子产生。综上所述，数据表明 MBD2 通过激活 PKCη/p38MAPK 和 ERK1/2 轴介导脓毒症诱发的 AKI。 MBD2 是治疗脓毒症 AKI 的潜在靶点。 MBD2 在脓毒性 AKI 中发挥着关键作用。从机制上讲，MBD2 激活 PKCη/p38MAPK 和 ERK1/2 轴，分别诱导肾细胞凋亡和炎症因子产生。数据表明 MBD2 可能是脓毒性 AKI 的潜在靶点。
Our previous study demonstrated that the methyl-CpG-binding domain protein 2 (MBD2) mediates vancomycin (VAN)-induced acute kidney injury (AKI). However, the role and regulation of MBD2 in septic AKI are unknown. Herein, MBD2 was induced by lipopolysaccharide (LPS) in Boston University mouse proximal tubules (BUMPTs) and mice. For both in vitro and in vivo experiments, we showed that inhibition of MBD2 by MBD2 small interfering RNA (siRNA) and MBD2-knockout (KO) substantially improved the survival rate and attenuated both LPS and cecal ligation and puncture (CLP)-induced AKI, renal cell apoptosis, and inflammatory factor production. Global genetic expression analyses and in vitro experiments suggest that the expression of protein kinase C eta (PKCη), caused by LPS, is markedly suppressed in MBD2-KO mice and MBD2 siRNA, respectively. Mechanistically, chromatin immunoprecipitation (ChIP) analysis indicates that MBD2 directly binds to promoter region CpG islands of PKCη via suppression of promoter methylation. Furthermore, PKCη siRNA improves the survival rate and attenuates LPS-induced BUMPT cell apoptosis and inflammatory factor production via inactivation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK)1/2, which were further verified by PKCη siRNA treatment in CLP-induced AKI. Finally, MBD2-KO mice exhibited CLP-induced renal cell apoptosis and inflammatory factor production by inactivation of PKCη/p38MAPK and ERK1/2 signaling. Taken together, the data indicate that MBD2 mediates septic-induced AKI through the activation of PKCη/p38MAPK and the ERK1/2 axis. MBD2 represents a potential target for treatment of septic AKI. MBD2 played a pivotal role in septic AKI. Mechanistically, MBD2 activated PKCη/p38MAPK and the ERK1/2 axis to induce renal cell apoptosis and inflammation factors production, respectively. The data suggested that MBD2 may be a potential target for septic AKI.
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