常染色体显性多囊肾病的昼夜节律紊乱与肾囊肿生长

IF 10.3 1区医学 Q1 UROLOGY & NEPHROLOGY

Journal of The American Society of Nephrology Pub Date : 2024-10-14 DOI:10.1681/ASN.0000000528

Abeda Jamadar, Christopher J Ward, Viji Remadevi, Meekha M Varghese, Navjot S Pabla, Michelle L Gumz, Reena Rao

引用次数: 0

摘要

背景：常染色体显性多囊肾病（ADPKD）是由PKD1和PKD2基因突变引起的，通常会发展为肾衰竭。ADPKD在患者中的进展并不一致，这表明PKD1/2基因突变的次要因素可能会调节疾病的进展速度。在此，我们测试了昼夜节律紊乱对 ADPKD 进展的影响。昼夜节律由时钟蛋白组成的细胞自主昼夜节律钟调控。BMAL1是昼夜节律钟的核心成分：为了破坏昼夜节律，我们在Pkd1RC/RC（RC/RC）ADPKD小鼠模型（RC/RC;Bmal1f/f;Pkhd1cre，称为DKO小鼠）的肾集合管和Pkd1基因敲除小鼠内髓集合管细胞（Pkd1Bmal1KO mIMCD3细胞）中删除了Bmal1基因。仅使用雄性小鼠：结果：与正常对照组相比，人类肾切除后的 ADPKD 肾脏显示出时钟基因表达的改变。与 RC/RC 肾脏相比，DKO 肾脏的时钟基因表达明显改变，囊肿生长、细胞增殖、细胞凋亡和纤维化增加。与 RC/RC 肾脏相比，DKO 肾脏还显示脂肪生成和胆固醇合成相关基因表达增加，组织甘油三酯水平升高。同样，在体外，与 Pkd1KO 细胞相比，Pkd1Bmal1KO 细胞的时钟基因发生改变，脂肪生成和胆固醇合成相关基因表达增加，脂肪酸氧化相关基因表达减少。与Pkd1KO细胞相比，Pkd1Bmal1KO细胞的细胞增殖增加，而药物抑制脂肪生成可以挽救这种增殖：结论：肾集合管特异性Bmal1基因缺失破坏了昼夜节律，并通过改变脂质代谢相关基因的表达引发了ADPKD的加速进展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

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.