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논문분류	춘계학술대회 초록집
제목	N6-methyladenosine-modified circNfix attenuates sepsis-induced acute kidney injury by facilitating the ubiquitination of YTHDF2 and increasing DAPK2 mRNA stability
저자	Peng Wang
출판정보	2024; 2024(1):
키워드
초록	Objectives: Increasing evidence shows that circRNAs play an important role in sepsis-induced acute kidney injury (SAKI). However, the mechanisms of circRNAs in SAKI have not been reported except the way of miRNA sponges. Notably, the function of N6-methyladenosine (m6A)-modified circRNA in SAKI remains undiscovered. Therefore, global profiles of circRNAs in kidneys with SAKI are needed, which will contribute to uncovering novel mechanisms underlying circRNAs in pathophysiology of SAKI. Methods: SAKI-associated circRNAs were screened via circRNA microarray and examined using in situ hybridization (ISH) in renal tissue. The role of circNfix in YTHDF2-induced pro-inflammatory or pro-apoptotic response of tubular epithelial cells (TECs) was assesed by luciferase reporter assay and Annexin V/ PI staining assay in vitro. Adeno-associated virus was used to deliver circNfix to the kidneys of SAKI mice to study the function of circNfix in vivo. The mechanism underlying circNfix-mediated activation of NF-κB signaling was examined by Mass spectrometry, RNA pull-down, MeRIP-qPCR and ISH. Results: circNfix expression was downregulated in TECs following SAKI, leading to apoptosis and inflammatory injury in TECs in vitro and in vivo. The downregulation of circNfix expression was post-transcriptionally attributed to the RNA splicing regulator RBM47. Mechanistically, circNfix was found to provide a scaffold for the interaction between YTHDF2 and HECTD1, which was augmented by circNfix N6-methyladenosine (m6A) modification, facilitating YTHDF2 ubiquitination and degradation. By decreasing the expression of YTHDF2, circNfix promoted the stabilization of DAPK2 mRNA, a negative regulator of NF-κB signaling, to protect LPS-induced TECs injury. Finally, restoring circNfix in an experimentally-induced mouse SAKI model suppressed NF-κB signaling, thereby improving renal function and ameliorating tubular injury. Conclusions: Collectively, m6A modified-circNfix suppresses NF-κB-driven renal inflammation via a YTHDF2-dependent mechanism during SAKI, and restoring circNfix might represent a therapeutic strategy for SAKI.
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