Role of miRNA-671-5p in Mediating Wnt/β-Catenin-Triggered Podocyte Injury

作者：Wang, Chunhong; Liu, Jiafeng; Zhang, Xiaoyao; Chen, Qiyan; Bai, Xiaoyan; Hong, Xue; Zhou, Lili^*; Liu, Youhua^*

来源：Frontiers in Pharmacology, 2022, 12: 784489.

DOI：10.3389/fphar.2021.784489

• podocyte injury
• Wnt
• beta-catenin
• miRNA-671-5p
• WT1
• proteinuria

Podocyte injury and proteinuria are the most common features of glomerular disease, which is the leading cause of end-stage renal failure. Hyperactivated Wnt/beta-catenin signaling is closely associated with podocyte injury, but the underlying mechanisms are incompletely understood. Here we show that miRNA-671-5p (miR-671-5p) plays a crucial role in mediating beta-catenin-triggered podocyte injury by targeting Wilms tumor 1 (WT1). Microarray-based expression profiling revealed that miR-671-5p was the most upregulated miRNA in podocytes after beta-catenin activation. MiR-671-5p was colocalized with beta-catenin in the glomeruli of proteinuric CKD in vivo. Bioinformatics analyses and luciferase reporter assays confirmed that miR-671-5p targeted WT1 mRNA. Overexpression of miR-671-5p mimics inhibited WT1 and impaired podocyte integrity, whereas miR-671-5p antagomir preserved the expression of WT1 and other podocyte-specific proteins under basal conditions or after beta-catenin activation. In mouse remnant kidney model, overexpression of miR-671-5p aggravated podocyte injury, worsened kidney dysfunction and exacerbated renal fibrosis after 5/6 nephrectomy. In contrast, miR-671-5p antagomir alleviated podocyte injury and attenuated proteinuria and renal fibrotic lesions after glomerular injury in vivo. These studies underscore a pivotal role of miR-671-5p in mediating WT1 depletion and podocyte injury induced by beta-catenin. Targeting miR-671-5p may serve as a new approach to prevent podocyte injury and proteinuria in proteinuric CKD.

• 单位
  南方医科大学