由YY1/HDAC2介导的RCAN1.4表达的干扰调节慢性脏异质移植间歇性纤维化
Jianjian Zhang1, Yao Zhang1, Dengyuan Feng1
1Department of Urology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 210029, Nanjing, China.
Cell death discovery
|July 28, 2023
概括
调节氨素1.4 (RCAN1.4) 通过抑制上皮层-介质细胞转换 (EMT) 来保护移植功能障碍. YY1-RCAN1.4轴为间歇性纤维化/管状缩 (IF/TA) 提供了一个新的治疗点.
科学领域:
- 腎臟病學 (nephrology) 是一種醫學專業.
- 移植免疫学 移植免疫学
- 分子生物学分子生物学
背景情况:
- 慢性异位移植功能障碍 (CAD) 显著降低了移植存活率.
- 表皮-介质细胞过渡 (EMT) 驱动间歇性纤维化/管状缩 (IF/TA),这是CAD的标志.
- 尿素1 (RCAN1) 表达的调节剂在脏疾病中发生变化,但其在CAD相关的IF/TA中的作用尚不清楚.
研究的目的:
- 调查RCAN1.4在CAD中IF/TA调节中的作用.
- 阐明RCAN1.4影响EMT和纤维化的分子机制.
- 为了确定潜在的治疗目标来缓解CAD.
主要方法:
- 为CAD建立了一个体内小鼠移植模型.
- 利用使用人管状上皮细胞 (HK-2) 治疗瘤死因子-α (TNF-α) 的体外模型.
- 评估了RCAN1.4表达,阴阳1 (YY1) 活性,EMT标记物,氧化应激和氨酸/NFATc1信号传递.
主要成果:
- 在CAD模型 (体内和体外) 中,RCAN1.4的表达减少,而YY1的表达增加.
- 通过调节抗氧化应激和氨酸/NFATc1信号传递,恢复RCAN1.4减弱的纤维化和抑制TNF-α诱导的EMT.
- YY1通过直接促进体相互作用负调节RCAN1.4转录,与HDAC2形成复合体,导致表观遗传抑制.
结论:
- 在CAD中,RCAN1.4通过调节氧化应激和氨氨酸/NFATc1通路,对IF/TA起着保护作用.
- YY1/HDAC2复合体在表观遗传上抑制RCAN1.4的转录,从而导致CAD的发病.
- YY1-RCAN1.4轴代表了治疗脏移植患者的IF/TA的新型治疗点.
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