Piezo1通过Ca2+依赖性calpain/HIF-1α/Notch信号通路加重缺血/再灌注诱导的急性肾损伤。

IF 3 3区 医学 Q1 UROLOGY & NEPHROLOGY
Renal Failure Pub Date : 2025-12-01 Epub Date: 2025-01-08 DOI:10.1080/0886022X.2024.2447801
Xiaoting Chen, Jintao Jiang, Bin He, Shangfei Luo, Qiaorui Tan, Youfen Yao, Rentao Wan, Honglin Xu, Silin Liu, Xianmei Pan, Xin Chen, Jing Li
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引用次数: 0

摘要

巨噬细胞在缺血/再灌注诱导的急性肾损伤(IR-AKI)的炎症和修复过程中发挥重要作用。机械敏感离子通道Piezo1在这些炎症过程中起重要作用。然而,巨噬细胞Piezo1在IR-AKI中的确切作用尚不清楚。本研究的主要目的是确定巨噬细胞Piezo1在IR-AKI损伤和修复过程中的作用。建立骨髓细胞靶向敲除Piezo1基因修饰小鼠,双侧肾血管夹持术诱导急性肾损伤。此外,体外对骨髓源性巨噬细胞进行缺氧处理。我们的数据表明,IR-AKI小鼠肾巨噬细胞中Piezo1表达上调。髓样Piezo1敲除对IR-AKI小鼠具有保护作用。从机制上讲,Piezo1对巨噬细胞的调节作用至少部分与钙蛋白酶信号传导有关。Piezo1激活Ca2+依赖性钙蛋白酶信号,其严重上调HIF-1α信号。这一关键通路随后影响Notch和CCL2/CCR2通路,驱动M1巨噬细胞的极化。总之,我们的研究结果阐明了Piezo1在肾巨噬细胞中的生物学功能,强调了其作为急性肾损伤的重要介质的作用。因此,Piezo1的遗传或药理学抑制提出了治疗IR-AKI的有希望的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Piezo1 aggravates ischemia/reperfusion-induced acute kidney injury by Ca2+-dependent calpain/HIF-1α/Notch signaling.

Macrophages play a vital role in the inflammation and repair processes of ischemia/reperfusion-induced acute kidney injury (IR-AKI). The mechanosensitive ion channel Piezo1 is significant in these inflammatory processes. However, the exact role of macrophage Piezo1 in IR-AKI is unknown. The main purpose of this study was to determine the role of macrophage Piezo1 in the injury and repair process in IR-AKI. Genetically modified mice with targeted knockout of Piezo1 in myeloid cells were established, and acute kidney injury was induced by bilateral renal vascular clamping surgery. Additionally, hypoxia treatment was performed on bone marrow-derived macrophages in vitro. Our data indicate that Piezo1 is upregulated in renal macrophages in mice with IR-AKI. Myeloid Piezo1 knockout provided protective effects in mice with IR-AKI. Mechanistically, the regulatory effects of Piezo1 on macrophages are at least partially linked to calpain signaling. Piezo1 activates Ca2+-dependent calpain signaling, which critically upregulates HIF-1α signaling. This key pathway subsequently influences the Notch and CCL2/CCR2 pathways, driving the polarization of M1 macrophages. In conclusion, our findings elucidate the biological functions of Piezo1 in renal macrophages, underscoring its role as a crucial mediator of acute kidney injury. Consequently, the genetic or pharmacological inhibition of Piezo1 presents a promising strategy for treating IR-AKI.

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来源期刊
Renal Failure
Renal Failure 医学-泌尿学与肾脏学
CiteScore
3.90
自引率
13.30%
发文量
374
审稿时长
1 months
期刊介绍: Renal Failure primarily concentrates on acute renal injury and its consequence, but also addresses advances in the fields of chronic renal failure, hypertension, and renal transplantation. Bringing together both clinical and experimental aspects of renal failure, this publication presents timely, practical information on pathology and pathophysiology of acute renal failure; nephrotoxicity of drugs and other substances; prevention, treatment, and therapy of renal failure; renal failure in association with transplantation, hypertension, and diabetes mellitus.
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