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针对MLL1/WDR5介导的表观遗传调节通过减少p16^INK4a来缓解腹膜纤维化

Daisuke Hara¹, Kensuke Sasaki¹, Shigehiro Doi¹

¹Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

|April 15, 2025

概括

准MLL1/WDR5复合体可减少细胞衰老和炎症,缓解小鼠和人类细胞中的腹膜纤维化. 这种方法对治疗腹膜透析并发症有前途.

科学领域:

细胞生物学细胞生物学
分子生物学分子生物学
腎臟病學 (nephrology) 是一種醫學專業.

背景情况:

腹膜纤维化是腹膜透析 (PD) 的一个主要并发症.
细胞衰老,特别是p16INK4a表达,在腹纤维化病原体中越来越被认可.
混合血统白血病1 (MLL1) / WD-40重复蛋白5 (WDR5) 复合体,一个基因组甲基转移酶,影响基因表达和细胞过程.

研究的目的:

研究MLL1/WDR5在腹衰老和纤维化中的作用.
确定抑制MLL1/WDR5是否可以减轻腹衰老,炎症和纤维化.
探索涉及p16INK4a和3 lysine 4三甲基化 (H3K4me3) 的基底分子机制.

主要方法:

评估了MLL1/WDR5,H3K4me3和p16INK4a表达在人腹膜间皮质细胞 (HPMC),PD患者样本和甲基酸盐 (MGO) 诱导的小鼠模型中.
使用MLL1/WDR5抑制剂 (MM-102,OICR-9429) 治疗细胞和注射MGO的小鼠.
分析了p16INK4a表达和透析剂/血肌素比率之间的相关性.
研究了MLL1/WDR5诱导的H3K4me3在p16INK4a基因转录中的直接调节作用.

主要成果:

在刺激的HPMC,PD患者细胞和MGO诱导的小鼠腹膜组织中观察到MLL1/WDR5,H3K4me3和p16INK4a的升高.
抑制MLL1/WDR5显著降低了H3K4me3和p16INK4a水平.
用抑制剂治疗抑制了注射MGO的小鼠的腹膜纤维化和炎症,并改善了腹膜功能.
证实MLL1/WDR5诱导的H3K4me3可以直接调节p16INK4a转录.

结论:

针对MLL1/WDR5复合体有效地减少腹衰老,炎症和纤维化.
抑制MLL1/WDR5为缓解PD患者腹纤维化提供了潜在的治疗策略.
这些发现阐明了一种涉及MLL1/WDR5,H3K4me3和p16INK4a在腹纤维化发展中的新机制.

关键词:

在MLL1/WDR5中使用.表观遗传学是指表观遗传学.腹膜透析是指腹膜透析.腹膜纤维化腹膜纤维化腹膜炎症是一种腹膜炎症.衰老是一种老化.

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