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

Autophagy plays a crucial role in the development and progres-sion of ischemic acute kidney injury (AKI). However, the func-tion and mechanism of circular RNAs (circRNAs) in the regu-lation 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. Overex-pression 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 phar-macological inhibitors is capable of reversing ZNF609-250aa-induced autophagy flux impairment and cell apoptosis in HK-2 cells. The present study demonstrates that highly ex-pressed 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.

Automated summary

This study revealed the crucial role of circular RNAs (circRNAs) in the regulation of autophagy in ischemic acute kidney injury (AKI). Specifically, circ-ZNF609, which is highly expressed in the kidney after ischemia/reperfusion injury, was found to activate AKT3/mTOR signaling and induce autophagy flux impairment and cell apoptosis. Mechanistically, circ-ZNF609 encodes a functional protein called ZNF609-250aa, which also promotes autophagy flux impairment and cell apoptosis. Targeting circ-ZNF609 may provide a novel therapy for ischemic AKI.