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糖尿病肾病斑马鱼模型表现为高血糖、蛋白尿和 PI3K/Akt 通路的激活。

A zebrafish model of diabetic nephropathy shows hyperglycemia, proteinuria and activation of the PI3K/Akt pathway.

机构信息

Graduate School of Regional Innovation Studies, Mie University, Tsu, Mie 514-8507, Japan.

Mie University Zebrafish Research Center, Tsu, Mie 514-8507, Japan.

出版信息

Dis Model Mech. 2024 May 1;17(5). doi: 10.1242/dmm.050438. Epub 2024 May 29.

DOI:10.1242/dmm.050438
PMID:38747698
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11152558/
Abstract

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.

摘要

糖尿病肾病（DN）作为糖尿病的一种并发症，由于其涉及的高发病率和死亡率，是一个重大的医疗保健挑战。尽管在理解 DN 的发病机制方面已经取得了重大进展，但仍需要更有效的模型来开发新的治疗方法。在这里，我们通过将糖尿病 Tg(acta1:dnIGF1R-EGFP)和蛋白尿示踪 Tg(l-fabp::VDBP-GFP)系杂交，在斑马鱼中创建了一个 DN 模型，命名为 zMIR/VDBP。过度喂养的成年 zMIR/VDBP 鱼会发展出严重的高血糖和蛋白尿，而在野生型斑马鱼中则没有观察到这些症状。肾脏组织病理学显示出类似于人类 DN 的特征，如肾小球基底膜增厚、足突融合和肾小球硬化。热量限制可恢复肾小球功能障碍。RNA 测序分析表明，DN 斑马鱼肾脏表现出与人类 DN 发病机制相似的转录模式。值得注意的是，DN 斑马鱼肾脏中激活了磷脂酰肌醇 3-激酶 (PI3K)/蛋白激酶 B (Akt)信号通路，这一现象在人类 DN 的早期阶段就已经观察到。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。我们的结果表明，zMIR/VDBP 鱼适合阐明人类 DN 的发病机制，并且可能成为治疗发现的有力工具。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/875e/11152558/253e00ada30d/dmm-17-050438-g8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/875e/11152558/253e00ada30d/dmm-17-050438-g8.jpg
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