抑制mTORC2通过降低NCC和ENaC活动,促进了对达尔盐敏感的老鼠的自然养
Chun Yang1, Elena Isaeva2, Satoshi Shimada1
1Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States.
American journal of physiology. Renal physiology
|May 23, 2024
概括
PP242是一种mTORC抑制剂,通过抑制NCC和ENaC载体,有效降低血压,并保护敏感盐的老鼠的脏. 这种双重作用为高血压和损伤提供了一个有前途的治疗策略.
科学领域:
- 科和高血压研究研究
- 移植体的分子药理学 移植体的分子药理学
- 猛素的哺乳动物目标 (mTOR) 信号通路
背景情况:
- 之前的研究表明,拉巴胺在对达尔盐敏感 (SS) 鼠群中部分降低了高血压和脏炎症.
- 双重mTORC1/mTORC2抑制剂PP242完全预防了高血压,并保护了SS大鼠的损伤.
- PP242显示出强烈的尿效应,与拉帕米辛不同.
研究的目的:
- 为了确定负责PP242在SS大鼠中产生尿作用的特定管状脏部位.
- 阐明PP242发挥抗高血压和保护作用的分子机制.
主要方法:
- 在正常或高盐饮食中的未经麻醉的SS大鼠中,急性给予PP242.
- 评估使用特定抑制剂的尿剂,利尿剂和尿剂反应:本扎米尔 (ENaC),罗塞米德 (NKCC2) 和化 (NCC).
- 分子分析以调查mTORC2调节NCC和ENaC活动.
主要成果:
- 在SS大鼠中,PP242的尿效应主要是由于抑制Na-Cl共运输体 (NCC) 和降低表皮Na+通道 (ENaC) 开放概率.
- 分子数据表明mTORC2通过酸化调节NCC活性,通过蛋白质分解裂变调节ENaC活性.
- PP242防止了与NCC抑制相关的损失,这表明节约效应.
结论:
- PP242抑制NCC并降低远端管状段中的ENaC活性,从而产生显著的自然尿和抗高血压作用.
- 在体内,mTORC2在调节NCC和ENaC功能方面发挥着至关重要的作用.
- PP242为对盐敏感个体的高血压和损伤管理提供了潜在的改善的治疗策略,因为它对输送器和潜在的节约性质的双重作用.
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