GADD45α是TFEB的直接标,有助于塔克罗利斯诱导的慢性毒性

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Ping Gao^1,2, Xinwei Cheng³, Maochang Liu²

¹School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China.

|February 6, 2025

概括

塔克罗利斯通过抑制转录因子EB (TFEB) 途径来损害脏. 激活TFEB及其标GADD45α可以防止这种塔克罗利斯诱导的慢性毒性.

科学领域:

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

背景情况:

塔克罗利木斯诱导的慢性毒性 (TICN) 限制了塔克罗利木斯的使用,但其机制尚不清楚.
塔克罗利马斯抑制氨酸,影响T细胞激活,但可能影响其他基质.
转录因子EB (TFEB) 是一种氨酸基质,对细胞平衡至关重要.

研究的目的:

调查TFEB在TICN中的作用.
确定涉及TICN的TFEB下游目标.
探索TFEB及其目标作为TICN的潜在治疗干预措施.

主要方法:

评估了TFEB核转位和活动在被塔克罗利斯治疗的小鼠脏和HK-2细胞中.
在HK-2细胞中利用了TFEB功能增益和丧失模型.
在TICN.的小鼠模型中通过酸化位点突变和激动剂激活了TFEB.
执行了ChIP-Seq以确定TFEB转录目标.
验证了GADD45α作为TFEB目标,使用了ChIP和双露西法酶记者测试.
过度表达的GADD45α在体外和体内,以评估其保护作用.

主要成果:

塔克罗利斯抑制了TFEB核转位和细胞和组织中的活性.
调节TFEB水平影响了塔克罗利斯诱导的细胞损伤.
在小鼠中,TFEB激活改善了TICN.
确定了增长停止和诱导DNA损伤的45α (GADD45α) 基因作为TFEB目标基因.
在体外和体内,GADD45α过度表达可以防止塔克罗利斯诱导的DNA损伤和损伤.

结论:

塔克罗利木斯诱导的慢性毒性是由TFEB/GADD45α通路的持续抑制介导的.
针对TFEB/GADD45α通路提供了一个潜在的治疗策略来缓解TICN.

关键词:

腎臟病學 (nephrology) 是一種醫學專業.治疗方法治疗方法毒理学毒理学毒理学

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