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NFATc3/LRRC55/BK通道通路对膜性肾病中足细胞细胞外基质重塑的调节作用

Modulation of podocyte extracellular matrix remodeling in membranous nephropathy by the NFATc3/LRRC55/BK channel pathway.

作者信息

Guo Yaling, Min Jingliang, Chang Baochao, Liu Lei, Zhang Jiqiang, Chen Weidong

机构信息

Department of Nephrology The First Affiliated Hospital of Jinan University Guangzhou Guangdong China.

Department of Nephrology The First Affiliated Hospital of Bengbu Medical University Bengbu China.

出版信息

J Cell Commun Signal. 2025 Jun 13;19(2):e70022. doi: 10.1002/ccs3.70022. eCollection 2025 Jun.

DOI:10.1002/ccs3.70022
PMID:40520074
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12165835/
Abstract

Membranous nephropathy (MN) is a common glomerular disease characterized by podocyte injury. Although previous studies highlighted the leucine-rich repeat-containing 55/big potassium (LRRC55/BK) channel axis in Ang II-induced apoptosis, our study further investigates the upstream regulation by nuclear factor of activated T-cells 3 (NFATc3) and its role in extracellular matrix (ECM) remodeling. Using an Ang II-induced podocyte injury model, we found that NFATc3 overexpression promoted LRRC55 transcription, increased BK channel activity, and elevated intracellular calcium, thereby exacerbating podocyte apoptosis and impairing migration. RNA-seq and functional assays revealed significant upregulation of ECM-related genes, with enhanced fibronectin and collagen I deposition. Patch-clamp experiments confirmed BK channel activation was LRRC55-dependent. In vivo, NFATc3 knockdown attenuated renal injury, restored podocyte markers (nephrin, WT1, synaptopodin), and alleviated proteinuria and fibrosis, whereas LRRC55 overexpression or BK agonist NS1619 reversed these effects. These findings reveal that NFATc3 aggravates Ang II-induced podocyte injury through transcriptional regulation of LRRC55 and activation of the BK channel, contributing to ECM remodeling and glomerular dysfunction. Our results offer mechanistic insight into MN progression and suggest the NFATc3/LRRC55/BK axis as a potential therapeutic target.

摘要

膜性肾病（MN）是一种以足细胞损伤为特征的常见肾小球疾病。尽管先前的研究强调了富含亮氨酸重复序列55/大钾通道（LRRC55/BK）轴在血管紧张素II诱导的细胞凋亡中的作用，但我们的研究进一步探讨了活化T细胞核因子3（NFATc3）的上游调控及其在细胞外基质（ECM）重塑中的作用。使用血管紧张素II诱导的足细胞损伤模型，我们发现NFATc3过表达促进LRRC55转录，增加BK通道活性，并升高细胞内钙，从而加剧足细胞凋亡并损害其迁移。RNA测序和功能分析显示ECM相关基因显著上调，纤连蛋白和I型胶原蛋白沉积增加。膜片钳实验证实BK通道激活依赖于LRRC55。在体内，敲低NFATc3可减轻肾损伤，恢复足细胞标志物（nephrin、WT1、突触足蛋白），并减轻蛋白尿和纤维化，而LRRC55过表达或BK激动剂NS1619可逆转这些作用。这些发现表明，NFATc3通过对LRRC55的转录调控和BK通道的激活加重血管紧张素II诱导的足细胞损伤，导致ECM重塑和肾小球功能障碍。我们的结果为MN的进展提供了机制性见解，并提示NFATc3/LRRC55/BK轴作为一个潜在的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a67e/12165835/af5be4d9fcc3/CCS3-19-e70022-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a67e/12165835/8a6a72fcfc95/CCS3-19-e70022-g004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a67e/12165835/a97ca00d5f7c/CCS3-19-e70022-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a67e/12165835/af5be4d9fcc3/CCS3-19-e70022-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a67e/12165835/8a6a72fcfc95/CCS3-19-e70022-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a67e/12165835/5e1659354416/CCS3-19-e70022-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a67e/12165835/ac08948ec3e1/CCS3-19-e70022-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a67e/12165835/b15fffc225c8/CCS3-19-e70022-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a67e/12165835/2065c70f09f3/CCS3-19-e70022-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a67e/12165835/a97ca00d5f7c/CCS3-19-e70022-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a67e/12165835/af5be4d9fcc3/CCS3-19-e70022-g005.jpg

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Cells. 2024 Dec 30;14(1):22. doi: 10.3390/cells14010022.
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Protective effect of compound K against podocyte injury in chronic kidney disease by maintaining mitochondrial homeostasis.复方K通过维持线粒体稳态对慢性肾脏病足细胞损伤的保护作用。
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Understanding the podocyte immune responses in proteinuric kidney diseases: from pathogenesis to therapy.
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Identification of hub genes and their correlation with immune infiltrating cells in membranous nephropathy: an integrated bioinformatics analysis.膜性肾病中枢纽基因的鉴定及其与免疫浸润细胞的相关性：一项综合生物信息学分析。
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Identification of Key Biomarkers Associated with Immunogenic Cell Death and Their Regulatory Mechanisms in Severe Acute Pancreatitis Based on WGCNA and Machine Learning.基于 WGCNA 和机器学习的严重急性胰腺炎中与免疫原性细胞死亡相关的关键生物标志物的鉴定及其调控机制。
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