开发新型糖尿病肾病斑马鱼模型。

IF 4 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2024-05-01 Epub Date: 2024-05-29 DOI:10.1242/dmm.050438
Liqing Zang, Sei Saitoh, Kan Katayama, Weibin Zhou, Norihiro Nishimura, Yasuhito Shimada
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引用次数: 0

摘要

糖尿病肾病(DN)是糖尿病的一种并发症,发病率和死亡率都很高,是医疗保健领域的一大挑战。尽管在了解糖尿病肾病的发病机制方面取得了重大进展,但仍需要更有效的模型来开发新的疗法。在这里,我们通过杂交糖尿病 Tg(acta1:dnIGF1R-EGFP)和蛋白尿追踪 Tg(l-fabp::VDBP-GFP)品系,建立了斑马鱼 DN 模型,命名为 zMIR/VDBP。过度喂养的zMIR/VDBP成鱼会出现严重的高血糖和蛋白尿,而野生型斑马鱼则不会出现这种情况。肾脏组织病理学显示出类似人类 DN 的特征,如肾小球基底膜增厚、足突脱出和肾小球硬化。限制热量摄入后,肾小球功能障碍会得到恢复。RNA 测序(RNA-seq)分析表明,斑马鱼 DN 肾脏表现出与人类 DN 发病机制相似的转录模式。值得注意的是,磷脂酰肌醇 3- 激酶(PI3K)/蛋白激酶 B(AKT)信号通路被激活,这是在人类 DN 早期阶段观察到的现象。此外,二甲双胍通过调节 AKT 磷酸化改善了 DN 斑马鱼的高血糖和蛋白尿。我们的研究结果表明,zMIR/VDBP鱼适合用于阐明人类DN的机制,并可作为发现治疗方法的有力工具。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A zebrafish model of diabetic nephropathy shows hyperglycemia, proteinuria and activation of the PI3K/Akt pathway.

Diabetic nephropathy (DN), as a complication of diabetes, is a substantial healthcare challenge owing to the high risk of morbidity and mortality involved. Although significant progress has been made in understanding the pathogenesis of DN, more efficient models are required to develop new therapeutics. Here, we created a DN model in zebrafish by crossing diabetic Tg(acta1:dnIGF1R-EGFP) and proteinuria-tracing Tg(l-fabp::VDBP-GFP) lines, named zMIR/VDBP. Overfed adult zMIR/VDBP fish developed severe hyperglycemia and proteinuria, which were not observed in wild-type zebrafish. Renal histopathology revealed human DN-like characteristics, such as glomerular basement membrane thickening, foot process effacement and glomerular sclerosis. Glomerular dysfunction was restored upon calorie restriction. RNA sequencing analysis demonstrated that DN zebrafish kidneys exhibited transcriptional patterns similar to those seen in human DN pathogenesis. Notably, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was activated, a phenomenon observed in the early phase of human DN. In addition, metformin improved hyperglycemia and proteinuria in DN zebrafish by modulating Akt phosphorylation. Our results indicate that zMIR/VDBP fish are suitable for elucidating the mechanisms underlying human DN and could be a powerful tool for therapeutic discovery.

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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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