Abstract: TH-PO065

MicroRNA671-5p Mediates Wnt/β-Catenin-Triggered Podocyte Injury by Targeting WT1

Session Information

Category: Glomerular

  • 1002 Glomerular: Basic/Experimental Pathology

Authors

  • Wang, Chunhong, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
  • Zhu, Wenjuan, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
  • Zhou, Lili, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
  • Liu, Youhua, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background

Podocyte injury is the major pathological feature of many proteinuric kidney diseases. It has been shown that dysregulated activation of Wnt/β-catenin signaling in podocytes can lead to podocyte dedifferentiation and mesenchymal transition, causing impaired glomerular filtration and proteinuria. MicroRNAs (miRNAs) are a class of short non-coding RNAs, which regulates specific genes by targeting and fine-tuning their expression. To study whether miRNA is involved in mediating Wnt/β-catenin-triggered podocyte injury, we performed a comprehensive miRNA expression profiling and sought to identify the miRNAs that may play a crucial role in this process.

Results

Mouse podocytes were transiently transfected with expression vector encoding constitutively activated β-catenin (pDel-β-cat) or empty vector (pcDNA3). The differential expression of miRNAs was identified through a microarray analysis. Among several dozens of miRNAs which expression levels were altered after β-catenin activation, miR-671-5p was on the top of the list. Subsequent qRT-PCR confirmed that miR-671-5p was upregulated in cultured podocytes after β-catenin activation, as well as in the kidneys of proteinuric CKD. Bioinformatics analysis predicted that miRNA671-5p could target WT1 mRNA for degradation. Indeed, over-expression of miR671-5p induced down-regulation of WT1 protein and promoted podocyte injury, whereas it had no effect on the level of WT1 mRNA. Inhibition of miRNA671-5p mitigated podocyte injury caused by β-catenin activation. In mouse model of remnant kidney after 5/6 nephrectomy (5/6NX), miR671-5p was specifically up-regulated in glomerular podocytes, as shown by in situ hybridization. Furthermore, over-expression of miR671-5p in vivo promoted β-catenin activation, inhibited WT1, worsened podocyte injury and kidney fibrotic lesions in remnant kidney after 5/6NX.

Conclusion

These studies identify miR-671-5p as a novel mediator that plays a crucial role promoting podocyte injury through down-regulation of WT1. The study also provides new insights into the pathogenic mechanisms of Wnt/β-catenin in podocyte dysfunction. Therefore, miR-671-5p may be a potential therapeutic target for ameliorating podocyte injury in the proteinuric kidney diseases.

Funding

  • NIDDK Support