Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
School of Life Science and Technology, Advanced Institute of Translational Medicine, Tongji University, Shanghai, China.
Am J Physiol Renal Physiol. 2023 Nov 1;325(5):F669-F680. doi: 10.1152/ajprenal.00287.2022. Epub 2023 Sep 21.
Mixed lineage leukemia 1 (MLL1) is a methyltransferase that induces histone H3 lysine 4 trimethylation (H3K4me3) and partially exerts its untoward functional effects by interacting with multiple subunits including menin and WD repeat-containing protein 5 (WDR5). In this study, we investigated the role and mechanisms of MLL1 in murine models of acute kidney injury induced by folic acid (FA) and ischemia-reperfusion. Injury to the kidney elevated the expression of MLL1, menin, WDR5, and H3K4Me3, which was accompanied by increased serum creatinine and blood urea nitrogen, renal tubular injury, and apoptosis. Pharmacological inhibition of MLL1 activity with MI503 to disrupt the interaction between MLL1 with menin further increased serum creatinine and blood urea nitrogen levels, enhanced expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, and induced more apoptosis in the kidney following FA and ischemia-reperfusion injury. In contrast, MI503 treatment decreased the expression of vimentin and proliferating cell nuclear antigens. Similarly, treatment with MM102 to disrupt the interaction between MLL1 and WDR5 also worsened renal dysfunction, aggravated tubular cell injury, increased apoptosis, and inhibited cellular dedifferentiation and proliferation in mice following FA injection. Moreover, MI503 inhibited FA-induced phosphorylation of epidermal growth factor receptor, signal transducer and activator of transcription 3, and extracellular signal-regulated kinase-1/2 in injured kidneys. Collectively, these data suggest that MLL1 contributes to renal protection and functional recovery and promotes renal regeneration through a mechanism associated with activation of the epidermal growth factor receptor signaling pathway. Mixed lineage leukemia 1 (MLL1) is a methyltransferase that induces histone H3 lysine 4 trimethylation and exerts its functional roles by interacting with multiple subunits. In this study, we demonstrated that inhibition of MLL1 activity by MI503 or MM102 aggravated renal injury and apoptosis and suppressed renal tubular cell dedifferentiation and proliferation, suggesting that MLL1 activation during acute kidney injury acts as an intrinsic protective mechanism to mediate renal tubular cell survival and regeneration.
混合谱系白血病 1（MLL1）是一种甲基转移酶，可诱导组蛋白 H3 赖氨酸 4 三甲基化（H3K4me3），并通过与包括门宁和 WD 重复蛋白 5（WDR5）在内的多个亚基相互作用来发挥其不良的功能效应。在这项研究中，我们研究了 MLL1 在叶酸（FA）和缺血再灌注诱导的急性肾损伤的小鼠模型中的作用和机制。肾脏损伤会升高 MLL1、门宁、WDR5 和 H3K4Me3 的表达，同时伴有血清肌酐和血尿素氮升高、肾小管损伤和细胞凋亡。用 MI503 抑制 MLL1 活性以破坏 MLL1 与门宁的相互作用进一步增加了血清肌酐和血尿素氮水平，增强了中性粒细胞明胶酶相关脂质运载蛋白和肾损伤分子-1 的表达，并在 FA 和缺血再灌注损伤后诱导肾脏更多的凋亡。相反，MI503 处理降低了波形蛋白和增殖细胞核抗原的表达。同样，用 MM102 破坏 MLL1 和 WDR5 之间的相互作用也会加重肾功能障碍、加重肾小管细胞损伤、增加凋亡，并抑制 FA 注射后小鼠细胞的去分化和增殖。此外，MI503 抑制 FA 诱导的损伤肾脏中表皮生长因子受体、信号转导和转录激活因子 3 和细胞外信号调节激酶 1/2 的磷酸化。总之，这些数据表明，MLL1 通过与表皮生长因子受体信号通路激活相关的机制，有助于肾脏保护和功能恢复，并促进肾脏再生。混合谱系白血病 1（MLL1）是一种甲基转移酶，可诱导组蛋白 H3 赖氨酸 4 三甲基化，并通过与多个亚基相互作用发挥其功能作用。在这项研究中，我们证明了 MI503 或 MM102 抑制 MLL1 活性会加重肾脏损伤和凋亡，并抑制肾小管细胞去分化和增殖，这表明急性肾损伤期间 MLL1 的激活作为一种内在的保护机制，介导肾小管细胞的存活和再生。
