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Abstract: PO1726

CircZNF609 Participates in the Pathogenesis of Focal Segmental Glomerulosclerosis by Sponging miR-615-5p

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Luan, Junjun, Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, China
  • Zhou, Hua, Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, China
Background

Focal segmental glomerulosclerosis (FSGS) is the most common cause of adult nephrotic syndrome, but its mechanism remains unclear. We recently identified and validated that circZNF609 increased in renal biopsies of lupus nephritis patients. We aim to verify whether circZNF609 participates in the pathogenesis of FSGS and the underlying mechanisms.

Methods

FSGS was induced by adramycin (ADR) injection to mice. Proteinuria and serum albumin were examined six weeks after ADR administration. Glomerulosclerosis and tubulointerstitial fibrosis were verified on PAS and Masson staining. Podocyte injury indicated with Wilms tumor 1(WT1) and Podocin, pro-fibrotic proteins including collagen 1 (COL1) and transforming growth factor-beta1 (TGF-β1) were analized by western blotting. Further, renal circZNF609 and miR-615 were measured by qPCR and fluorescence in situ hybridization (FISH). The correlation between renal circZNF609 and above indices were analyzed.In vitro study, circZNF609 in bovine serum albumin (BSA) stimulated HK2 cells for 24 h, which mimic the toxicity of proteinuria from FSGS to tubules. CircZNF609, miR-615, COL1 and TGF-β1 were analyzed by qPCR. Lastly, The renal localization of circZNF609 in FSGS patients was stained by FISH.

Results

In vivo study, proteinuria and hypoalbuminemia were found six weeks after FSGS onset by ADR injection. Glomerulosclerosis and tubulointerstitial fibrosis showed on PAS and Masson staining. CircZNF609 was upregulated while miR-615-5p was downregulated in FSGS mice analyzed by qPCR and FISH. Podocyte proteins WT1 and Podocin were decreased; pro-fibrotic proteins COL-1 and TGF-β1 were increased on western blotting. Renal circZNF609 positively correlated and miR-615-5p negatively correlated with podocyte injury and renal fibrosis. Importantly, circZNF609 and miR-615-5p co-localized on glomeruli and tubules on FISH. Perfect match seeds were found between circZNF609 and miR-615-5p and COL-1. In vitro study, circZNF609 increased and miR-615-5p decreased after BSA stimulation and negatively correlated between each other. COL-1 and TGF-β1 were upregulated and negatively correlated with miR-615-5p. Lastly, circZNF609 was confirmed to increase in glomeruli and tubules in renal biopsies from FSGS patients.

Conclusion

We conclude that circZNF609 may play an important role in FSGS by sponging miR-615-5p and may be a novel therapeutic target.

Funding

  • Government Support - Non-U.S.