Journal Article Epublish
PubMed: 40520074 DOI: 10.1002/ccs3.70022
Modulation of podocyte extracellular matrix remodeling in membranous nephropathy by the NFATc3/LRRC55/BK channel pathway.
J Cell Commun Signal 19(2):e70022
Authors: Yaling Guo, Jingliang Min, Baochao Chang, Lei Liu, Jiqiang Zhang, Weidong Chen
Affiliations
- 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.
- Department of Neurosurgery The Second Affiliated Hospital of Bengbu Medical University Bengbu China.
- Department of Nephrology The First Affiliated Hospital of Bengbu Medical University Bengbu China.
- Department of Nephrology The First Affiliated Hospital of Jinan University Guangzhou Guangdong China.
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.
MeSH
Glomerulonephritis, Membranous, Podocytes, Large-Conductance Calcium-Activated Potassium Channels, Apoptosis, Extracellular Matrix