p21活化激酶4与小鼠和人的缺血性急性肾损伤。

IF 10.3 1区 医学 Q1 UROLOGY & NEPHROLOGY
Hwang Chan Yu, Byeoung Hoon Chung, Yoejin Kim, Yoonji Lee, Hyunchae Sim, Sangkyu Lee, Hong Pil Hwang, Hee Chul Yu, Seunggyu Jeon, Han-Joo Maeng, Dongyun Shin, Kyung Pyo Kang, Seung-Yong Seo, Eun Ju Bae, Byung-Hyun Park
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引用次数: 0

摘要

背景:缺血再灌注后急性肾损伤仍然是围手术期的一个重大挑战,缺乏有效的治疗方法。p21活化激酶4 (PAK4)是Rho GTPase的下游效应物,在肝脏缺血再灌注损伤中已被发现,但在肾缺血再灌注中的作用尚不清楚。方法:野生型和近端小管特异性Pak4敲除小鼠缺血25 min,再灌注24 h。将原代小管细胞和HK-2细胞暴露于缺氧-再氧化损伤中,研究PAK4在体外的影响。利用蛋白水解靶向嵌合体(proteolysis-targeting chimeras, PROTAC)选择性降解PAK4来改善急性肾损伤。结果:缺血再灌注后,PAK4通过缺氧诱导因子1 α在小鼠肾脏中表达上调。PAK4在近端小管细胞中缺失,而在髓细胞中缺失,可显著减轻缺血再灌注引起的急性肾损伤,与对照小鼠相比,血尿素氮、肌酐、小管坏死、凋亡、巨噬细胞浸润和脂质积累水平降低。进一步研究发现PAK4在T47位点磷酸化谷胱甘肽过氧化物酶3,导致其蛋白酶体降解。此外,用PAK4 PROTAC预处理小鼠可保存谷胱甘肽过氧化物酶3,增强脂肪酸β-氧化,从而保护急性肾损伤。在肾移植患者的肾组织中,观察到PAK4蛋白水平升高和谷胱甘肽过氧化物酶3在T47位点的磷酸化。结论:肾小管PAK4参与缺血-再灌注损伤时的组织损伤,而PAK4 PROTAC通过降低氧化应激、促进脂肪酸β-氧化来减轻缺血-再灌注损伤。
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p21-Activated Kinase 4 and Ischemic Acute Kidney Injury in Mice and Humans.
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来源期刊
Journal of The American Society of Nephrology
Journal of The American Society of Nephrology 医学-泌尿学与肾脏学
CiteScore
22.40
自引率
2.90%
发文量
492
审稿时长
3-8 weeks
期刊介绍: The Journal of the American Society of Nephrology (JASN) stands as the preeminent kidney journal globally, offering an exceptional synthesis of cutting-edge basic research, clinical epidemiology, meta-analysis, and relevant editorial content. Representing a comprehensive resource, JASN encompasses clinical research, editorials distilling key findings, perspectives, and timely reviews. Editorials are skillfully crafted to elucidate the essential insights of the parent article, while JASN actively encourages the submission of Letters to the Editor discussing recently published articles. The reviews featured in JASN are consistently erudite and comprehensive, providing thorough coverage of respective fields. Since its inception in July 1990, JASN has been a monthly publication. JASN publishes original research reports and editorial content across a spectrum of basic and clinical science relevant to the broad discipline of nephrology. Topics covered include renal cell biology, developmental biology of the kidney, genetics of kidney disease, cell and transport physiology, hemodynamics and vascular regulation, mechanisms of blood pressure regulation, renal immunology, kidney pathology, pathophysiology of kidney diseases, nephrolithiasis, clinical nephrology (including dialysis and transplantation), and hypertension. Furthermore, articles addressing healthcare policy and care delivery issues relevant to nephrology are warmly welcomed.
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