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

IF 3.6 3区生物学 Q3 CELL BIOLOGY

Journal of Cell Communication and Signaling Pub Date : 2025-06-13 DOI:10.1002/ccs3.70022

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

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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.

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

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。虽然之前的研究强调了富含亮氨酸的重复-含55/大钾（LRRC55/BK）通道轴在Ang ii诱导的细胞凋亡中起作用，但我们的研究进一步探讨了活化t细胞3 （NFATc3）的核因子上游调控及其在细胞外基质（ECM）重塑中的作用。通过Ang 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，升高细胞内钙，从而加剧足细胞凋亡和损害迁移。RNA-seq和功能分析显示，ecm相关基因显著上调，纤维连接蛋白和I型胶原沉积增强。膜片钳实验证实BK通道激活依赖于lrrc55。在体内，NFATc3敲低可减轻肾损伤，恢复足细胞标记物（nephrin, WT1, synaptopodin），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通过转录调控LRRC55和激活BK通道，加重Ang ii诱导的足细胞损伤，促进ECM重塑和肾小球功能障碍。我们的研究结果提供了MN进展的机制，并提示NFATc3/LRRC55/BK轴是一个潜在的治疗靶点。

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来源期刊

Journal of Cell Communication and Signaling CELL BIOLOGY-

CiteScore

6.40

自引率

4.90%

发文量

期刊介绍： The Journal of Cell Communication and Signaling provides a forum for fundamental and translational research. In particular, it publishes papers discussing intercellular and intracellular signaling pathways that are particularly important to understand how cells interact with each other and with the surrounding environment, and how cellular behavior contributes to pathological states. JCCS encourages the submission of research manuscripts, timely reviews and short commentaries discussing recent publications, key developments and controversies. Research manuscripts can be published under two different sections : In the Pathology and Translational Research Section (Section Editor Andrew Leask) , manuscripts report original research dealing with celllular aspects of normal and pathological signaling and communication, with a particular interest in translational research. In the Molecular Signaling Section (Section Editor Satoshi Kubota) manuscripts report original signaling research performed at molecular levels with a particular interest in the functions of intracellular and membrane components involved in cell signaling.