A protein encoded by circular ZNF609 RNA induces acute kidney injury by activating the AKT/mTOR-autophagy pathway.

Abstract

Autophagy plays a crucial role in the development and progression of ischemic acute kidney injury (AKI). However, the function and mechanism of circular RNAs (circRNAs) in the regulation of autophagy in ischemic AKI remain unexplored. Herein, we find that circ-ZNF609, originating from the ZNF609 locus, is highly expressed in the kidney after ischemia/reperfusion injury, and urinary circ-ZNF609 is a moderate predictor for AKI in heart disease patients. Overexpression of circ-ZNF609 can activate AKT3/mTOR signaling and induce autophagy flux impairment and cell apoptosis while inhibiting proliferation in HK-2 cells, which is blocked by silencing circ-ZNF609. Mechanistically, circ-ZNF609 encodes a functional protein consisting of 250 amino acids (aa), termed ZNF609-250aa, the overexpression of which can activate AKT3/mTOR signaling and induce autophagy flux impairment and cell apoptosis in HK-2 cells in vitro and in AKI kidneys in vivo. The blockade of AKT and mTOR signaling with pharmacological inhibitors is capable of reversing ZNF609-250aa-induced autophagy flux impairment and cell apoptosis in HK-2 cells. The present study demonstrates that highly expressed circ-ZNF609-encoded ZNF609-250aa induces cell apoptosis and AKI by impairing the autophagy flux via an AKT/mTOR-dependent mechanism. These findings imply that targeting circ-ZNF609 may be a novel therapy for ischemic AKI.

• Authors: Xin Ouyang, Zhimei He, Heng Fang, Huidan Zhang, Qi Yin, Linhui Hu, Fei Gao, Hao Yin, Taofang Hao, Yating Hou, Qingrui Wu, Jia Deng, Jing Xu, Yirong Wang, Chunbo Chen
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 31 Issue 6 Pg. 1722-1738 (Jun 07 2023) ISSN: 1525-0024 [Electronic] United States
• PMID: 36110046 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• Proto-Oncogene Proteins c-akt
• RNA, Circular
• TOR Serine-Threonine Kinases

Topics

• Humans
• Acute Kidney Injury (genetics)
• Apoptosis (genetics)
• Autophagy (genetics)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• RNA, Circular (genetics, metabolism)
• TOR Serine-Threonine Kinases (genetics, metabolism)