TRIM27 Alleviates AKI by Reducing GLIS1 DNA Methylation and Promoting GLIS1 Expression through Inhibiting PRC2 Activity

Background: Proliferation of dedifferentiated renal tubular epithelial cells (RTECs) is a major cellular event that contributes to renal repair after renal ischemia and reperfusion injury (RIRI)-induced acute kidney injury (AKI). Nevertheless, the underlying mechanism that initiates RTEC dedifferentiation remains unknown. Herein, the role of tri-domain proteins 27 (TRIM27) in the progression of RIRI-induced AKI was investigated. Methods: The animal model of RIRI-induced AKI was established by IRI, and mRTECs were treated with H2O2 to establish a cell injury model in vitro. The pathological changes in kidney tissues were assessed using HE and PAS staining. Cell viability and migration were assessed by CCK-8 assay and wound healing assay, respectively. Flow cytometry was employed to determine cell apoptosis. Co-IP assay was employed to analyze the interaction between TRIM27 and EZH2. The interaction between DNMT1 and GLIS1 was analyzed by ChIP assay. Results: TRIM27 expression was reduced in kidney tissues of IRI mice and H2O2-treated mRECs. TRIM27 overexpression enhanced mRTEC dedifferentiation, proliferation, and migration while inhibiting apoptosis after H2O2 treatment. Mechanistically, TRIM27 reduced PRC2 activity in mRTECs by mediating EZH2 ubiquitination degradation. PRC2 reduced GLIS1 expression in mRTECs through mediating H3K27me3 and DNA methylation. TRIM27 overexpression ameliorated IRI-induced AKI in mice by enhancing mRTEC dedifferentiation. Conclusion: TRIM27 upregulation alleviated RIRI-induced AKI by reducing GLIS1 DNA methylation and promoting GLIS1 expression through inhibiting PRC2 activity.