Abstract: FR-PO1201
Rolling-Translation of circVMP1 Promotes Proteinuric Nephropathy by Inhibiting Autophagy in Tubular Epithelial Cells
Session Information
- CKD: Mechanisms - 2
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Wang, Peng, Department of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Ma, Tongtong, The Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
Background
Proteinuria promotes the progression of chronic kidney disease (CKD) to end-stage renal disease by impairing tubular epithelial cells (TECs). Recent studies have found that autophagy and circRNAs play important roles in injured TECs. However, the functions and molecular mechanisms of circRNAs in autophagy and CKD progression is largely unclear. Our previous work revealed a novel mechanism, by which circBNC2 regulated cell cycle progression through encoding a previously unidentified protein, BNC2-681aa. However, whether circRNA mediates autophagy by translation remained to be elucidated.
Methods
High-throughput sequencing was carried out to identify differentially expressed circRNA in albumin-stimulated HK2 cells. The expression level of one candidate circRNA, circVMP1, was analyzed using Northern blot, FISH and real-time PCR. The effects of circVMP1 on autophagy was evaluated using TEM, RFP-GFP-LC3 cells. The encoding capacity of circVMP1 was proved through LC/MS and IRES reporter assay. After the validation of VMP1-143aa with a customized monoclonal antibody, the proteins that interact with VMP1-143aa was identified by LC/MS and Co-IP assays. Tubule-specific circVMP1 knockout mice were generated by crossing circVMP1f/f mice with Ksp-Cre mice.
Results
The expression level of circVMP1 in albumin-stimulated HK2 cells and biopsy samples from CKD patients with proteinuria was elevated. Knocking out circVMP1 in TECs alleviated renal inflammatory injury by promoting TECs autophagy in mouse adriamycin nephropathy model. Mechanistically, circVMP1 was found to inhibited TECs autophagy by translating a novel protein VMP1-143aa to function as a molecular decoy by interacting with BECN1 and TP53INP2, thereby inhibiting the function of VMP1 protein.
Conclusion
Collectively, circVMP1 promotes renal inflammatory injury in proteinuric nephropathy by hindering autophagy flux in a translation-dependent manner. Therefore, targeting circVMP1 or it’s translation product, VMP1-143aa, might provide a potential angle for proteinuric nephropathy by restoring TECs autophagy.
Funding
- Government Support – Non-U.S.