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肾组织来源的外泌体 miRNA-34a 通过促进 M1 巨噬细胞极化诱导糖尿病肾病肾小管细胞纤维化。

Renal Tissue-Derived Exosomal miRNA-34a in Diabetic Nephropathy Induces Renal Tubular Cell Fibrosis by Promoting the Polarization of M1 Macrophages.

机构信息

Department of Nephrology, The Second Affiliated Hospital, Kunming Medical University, No. 347 Dianmian Street, Kunming, Yunnan 650101, China.

出版信息

IET Nanobiotechnol. 2024 Apr 17;2024:5702517. doi: 10.1049/2024/5702517. eCollection 2024.

DOI:10.1049/2024/5702517
PMID:38863972
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11095076/
Abstract

BACKGROUND

Diabetic nephropathy (DN) is the leading cause of chronic kidney disease, and the activation and infiltration of phagocytes are critical steps of DN. This study aimed to explore the mechanism of exosomes in macrophages and diabetes nephropathy and the role of miRNA-34a, which might provide a new path for treating DN.

MATERIALS AND METHODS

The DN model was established, and the success of the model establishment was confirmed by detecting general indicators, HE staining, and immunohistochemistry. Electron microscopy and NanoSight Tracking Analysis (NTA) were used to see the morphology and size of exosomes. MiRNA-34a inhibitor, miRNA-34a mimics, pc-, and controls were transfected in macrophages with or without kidney exosomal. A dual-luciferase reporter gene experiment verifies the targeting relationship between miRNA-34a and . After exosomal culture, macrophages are co-cultured with normal renal tubular cells to detect renal tubular cell fibrosis. Q-PCR and western blot were undertaken to detect related RNA and proteins.

RESULTS

An animal model of diabetic nephropathy was successfully constructed. Macrophages could phagocytose exosomes. After ingesting model exosomes, M1 macrophages were activated, while M2 macrophages were weakened, indicating the model mice's kidney exosomes caused the polarization. MiRNA-34a inhibitor increased expression. MiRNA-34a expressed higher in diabetic nephropathy Model-Exo. MiRNA-34a negatively regulated . rescued macrophage polarization and renal tubular cell fibrosis.

CONCLUSION

Exosomal miRNA-34a of tubular epithelial cells promoted M1 macrophage activation in diabetic nephropathy via negatively regulating expression, which may provide a new direction for further exploration of DN treatment.

摘要

背景

糖尿病肾病（DN）是慢性肾脏病的主要病因，吞噬细胞的激活和浸润是 DN 的关键步骤。本研究旨在探讨巨噬细胞和糖尿病肾病中外泌体的作用机制及微小 RNA-34a（miRNA-34a）的作用，为治疗 DN 提供新途径。

材料与方法

建立糖尿病肾病模型，通过检测一般指标、HE 染色和免疫组化来验证模型建立的成功。电子显微镜和纳米粒子跟踪分析（NanoSight Tracking Analysis，NTA）用于观察外泌体的形态和大小。在有无肾脏外泌体的情况下，将 miRNA-34a 抑制剂、miRNA-34a 模拟物、pc-和对照物转染入巨噬细胞中。双荧光素酶报告基因实验验证 miRNA-34a 与 的靶向关系。在外泌体培养后，将巨噬细胞与正常肾小管细胞共培养，检测肾小管细胞纤维化。采用 Q-PCR 和 Western blot 检测相关 RNA 和蛋白。

结果

成功构建了糖尿病肾病动物模型。巨噬细胞可以吞噬外泌体。摄取模型外泌体后，M1 巨噬细胞被激活，而 M2 巨噬细胞被削弱，表明模型小鼠的肾脏外泌体引起了极化。miRNA-34a 抑制剂增加了 的表达。糖尿病肾病模型-外泌体中 miRNA-34a 表达较高。miRNA-34a 负调控 。miRNA-34a 表达下调可挽救巨噬细胞极化和肾小管细胞纤维化。

结论

肾小管上皮细胞外泌体 miRNA-34a 通过负调控 表达促进糖尿病肾病中 M1 巨噬细胞的激活，这可能为进一步探索 DN 的治疗提供新方向。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/581f/11095076/0f85eb5605ff/IETNBT2024-5702517.007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/581f/11095076/479eae7d37a8/IETNBT2024-5702517.001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/581f/11095076/0f85eb5605ff/IETNBT2024-5702517.007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/581f/11095076/479eae7d37a8/IETNBT2024-5702517.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/581f/11095076/b80330b79b84/IETNBT2024-5702517.002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/581f/11095076/a1692c881ae9/IETNBT2024-5702517.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/581f/11095076/0f85eb5605ff/IETNBT2024-5702517.007.jpg

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