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Abstract: PO0397

circBNC2 Inhibits Renal Fibrosis Through Regulating G2/M Cell Cycle Transition

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Author

  • Wang, Peng, Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangzhou, China
Background

Emerging evidence indicates that AKI is a causative factor for subsequent development of chronic kidney disease (CKD). G2/M cell cycle arrest of TECs promotes AKI to CKD progression, but the regulation of G2/M cell cycle arrest of TECs is largely unclear. Circular RNAs (circRNAs), a class of noncoding RNA, are recently found to be dysregulated in tubular epithelial cells (TECs) during renal ischemia/reperfusion (I/R) injury. However, the effects and underlying mechanisms of circRNAs in the progression of renal fibrosis are largely unrevealed.

Methods

Mild-AKI (20 min- IRI) and severe-AKI (40 min-IRI) were performed in C57BL/6 mice. The expression of circRNA were analyzed in the freshly isolated tubules from these mice by RNA-seq. One of the dysregulated circRNA, circBNC2 were identified and analyzed by Northern blot, FISH and real-time qPCR in HK2 cells, mouse primary TECs and in mouse kidney. HK-2 cells were exposed to hypoxia as in vitro model. To study the function of circBNC2, we used the CRISPR-Cas9 genome editing system to specifically knocked out circBNC2 in HK2, while circBNC2 was overexpression by plasmid. To study the function of circBNC2 in vivo, we applied adeno-associated virus (AAV)-based circBNC2 overexpression in C57BL/6 mice 3 weeks before performing IRI model. G2/M cell cycle arrest and pro-fibrotic cytokine expression were evaluated in HK2 and primary TECs. Renal fibrosis was evaluated in mouse kidney sections.

Results

The un-biased sequencing showed significant down-regulation of circBNC2 in TECs from severe-IRI mice, as compared to the TECs from mild-IRI mice and control mice. Knockout circBNC2 in HK2 and primary TECs led to G2/M cell cycle arrest and pro-fibrotic cytokines expression. While overexpression of circBNC2 decreased hypoxia-induced G2/M cell cycle arrest of TECs. Preventative overexpression of circBNC2 in vivo ameliorated 40 min-IRI induced renal fibrosis.

Conclusion

Our results showed that circBNC2 regulated G2/M cell cycle transition of TECs and might be served as a therapeutic target for AKI-progressed CKD.

Funding

  • Government Support – Non-U.S.