通过调节HRAS棕化,ZDHHC18促进纤维化的发展
Di Lu1, Gulibositan Aji2, Guanyu Li1
1Nephrology Department, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
The Journal of clinical investigation
|February 6, 2025
概括
ZDHHC18蛋白在纤维化中升高,并通过激活HRAS信号来驱动疾病的进展. 向ZDHHC18可能为打击慢性病 (CKD) 提供了一种新的策略.
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
- 生物化学 生物化学
背景情况:
- 纤维化是末期慢性病 (CKD) 的关键因素.
- 蛋白棕化在纤维化中的作用尚不清楚.
研究的目的:
- 为了研究ZDHHC18在纤维化中的功能.
- 阐明ZDHHC18在纤维化中的作用的潜在分子机制.
主要方法:
- 使用单边尿路阻塞 (UUO) 和叶酸诱导 (FA诱导) 纤维化的小鼠模型.
- 在小鼠模型和人类CKD脏中检查了ZDHHC18表达.
- 研究了ZDHHC18缺失和过度表达对纤维化的影响.
- 分析了涉及HRAS棕化和下游信号通路 (MEK/ERK,RREB1) 的分子机制.
主要成果:
- 从小鼠模型和人类CKD患者的纤维化脏中显著增加了ZDHHC18表达.
- ZDHHC18的管体特异性缺失减弱了表皮细胞-介质细胞过渡 (EMT),减少了益纤维细胞因子,并减轻了管体间纤维化.
- 过度表达ZDHHC18导致纤维化恶化.
- ZDHHC18催化HRAS棕化,促进其膜转位和激活,导致增强的MEK/ERK酸化和RREB1激活,这反过来又促进SMAD与Snai1调节区域结合.
结论:
- ZDHHC18在促进纤维化方面发挥着至关重要的作用.
- 由ZDHHC18介导的HRAS棕化是驱动纤维化的关键机制.
- ZDHHC18代表了治疗纤维化和CKD的潜在治疗标.
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