内皮功能障碍通过促进巨细胞中的β-catenin激活来加速AKI-to-CKD过渡
Masanobu Takasu1, Seiji Kishi1,2, Hajime Nagasu1
1Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Japan.
American journal of physiology. Renal physiology
|November 21, 2025
概括
内皮功能障碍在急性损伤后驱动纤维化,通过通过Wnt/β-catenin信号传递促进M2巨细胞的激活. 用PDE5抑制剂准这种途径可以防止慢性病的进展.
科学领域:
- 腎臟病學 (nephrology) 是一種醫學.
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
背景情况:
- 急性损伤 (AKI) 通常会发展为慢性病 (CKD),导致长期功能障碍.
- 内皮功能障碍,特别是涉及内皮氧化合成酶 (eNOS),是这种过渡过程中的关键调解者.
- 缺陷的氧化 (NO) - 循环瓜诺辛单酸盐 (cGMP) - 蛋白激酶G (PKG) 信号,通过维持β-catenin活性,加剧纤维化.
研究的目的:
- 调查内皮功能障碍和巨细胞极化在AKI到CKD进展中的作用.
- 阐明连接eNOS缺陷,β-catenin信号传递和M2巨细胞活化的机制.
- 评估向NO-cGMP-β-catenin通路在AKI到CKD过渡中的治疗潜力.
主要方法:
- 采用了患有或没有eNOS缺乏症的脑缺血-再输液损伤 (IRI) 的小鼠模型.
- 采用RNA测序和流细胞测量来分析巨细胞群和IRI后的基因表达特征.
- 研究了巨细胞枯竭和cGMP信号传递 (PDE5抑制剂) 的药理增强对纤维化和功能的影响.
主要成果:
- eNOS缺乏导致持续的β-catenin激活和持续的M2巨细胞极化超过IRI后的第7天.
- 实验室研究表明,NO-cGMP-PKG信号通过β-catenin降解抑制IL-4诱导的M2极化.
- 在ENOS缺乏的小鼠中,巨细胞枯竭减少了纤维化和改善了功能; PDE5抑制剂治疗改善了IRI后的纤维化.
结论:
- 内皮功能障碍通过Wnt/β-catenin激活促进了益菌性M2巨细胞表型,有助于AKI-to-CKD的进展.
- 持续的M2巨细胞激活在AKI后的纤维化中起着关键的病原作用.
- 针对NO-cGMP-β-catenin信号通路,例如使用PDE5抑制剂,代表了一种有希望的治疗策略,以防止AKI后的CKD进展.
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