Jia Xia, Yutong Hou, Jie Wang, Jiahui Zhang, Jiajia Wu, Xiang Yu, Hong Cai, Wen Yang, Yingjie Xu, Shan Mou
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引用次数: 0
摘要
背景:肾纤维化,细胞外基质的过度积累和失调重塑,是慢性肾脏疾病(CKD)的主要病理生理过程。蛋白质l -异天冬氨酸/ d -天冬氨酸甲基转移酶(PCMT1)在修复l -异天冬氨酸残基的翻译后修饰中起着至关重要的作用,这是因为它们的低周转率和对加速因子的敏感性对细胞外基质蛋白很重要。本研究旨在揭示PCMT1在肾纤维化中的新作用。方法:测定小鼠和人肾组织PCMT1的表达及其与纤维化和肾功能的关系。分析PCMT1对TGF-β1/Smad信号的影响,并在肾纤维化小管特异性PCMT1敲除小鼠模型中评估其功能作用。通过免疫沉淀、基因慢病毒过表达或敲除以及翻译后修饰质谱法研究分泌PCMT1修复转化生长因子β受体2 (TGFBR2)外域l -异天冬氨酸残基的能力。结果:CKD患者和小鼠纤维化模型的人肾活检小管中PCMT1表达降低。小鼠肾纤维化模型中肾小管特异性PCMT1缺失加重了肾小管损伤、细胞外基质蛋白沉积、肌成纤维细胞活化和TGF-β1/Smad信号过度激活。机制上,PCMT1在体外异常分泌,酶促抑制TGF-β1诱导的细胞外基质蛋白沉积。PCMT1与TGFBR2相互作用,逆转其外域N63的脱胺作用,从而引发TGFBR2泛素化和降解。在肾脏中补充PCMT1可降低TGFBR2水平,减弱TGF-β1/Smad的过度激活,并阻碍纤维化过程。结论:我们的研究强调了PCMT1通过调节TGFBR2脱氨及其蛋白稳定性,抑制TGF-β1/Smad信号传导,在维持细胞外基质稳态和减轻肾纤维化中的重要性。
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.