REST contributes to AKI-to-CKD transition through inducing ferroptosis in renal tubular epithelial cells

Ischemic-reperfusion injury (IRI) is a major pathogenic factor in acute kidney injury (AKI), which directly leads to the hypoxic injury of renal tubular epithelial cells (RTECs). Although emerging studies suggest repressor element 1-silencing transcription factor (REST) as a master regulator of gene repression under hypoxia, its role in AKI remains elusive. Here, we found that REST was upregulated in AKI patients, mice, and RTECs, which was positively associated with the degree of kidney injury, while renal tubule-specific knockout of Rest significantly alleviated AKI and its progression to chronic kidney disease (CKD). Subsequent mechanistic studies indicated that suppression of ferroptosis was responsible for REST-knockdown-induced amelioration of hypoxia-reoxygenation injury, during which process Cre-expressing adenovirus-mediated REST downregulation attenuated ferroptosis through upregulating glutamate-cysteine ligase modifier subunit (GCLM) in primary RTECs. Further, REST transcriptionally repressed GCLM expression via directly binding to its promoter region. In conclusion, our findings revealed the involvement of REST, a hypoxia regulatory factor, in AKI-to-CKD transition and identified the ferroptosis-inducing effect of REST, which may serve as a promising therapeutic target for ameliorating AKI and its progression to CKD.

Automated summary

Ischemic-reperfusion injury (IRI) is a major factor in acute kidney injury (AKI) that leads to hypoxic injury of renal tubular epithelial cells (RTECs). The upregulation of repressor element 1-silencing transcription factor (REST) in AKI patients, mice, and RTECs is positively correlated with the severity of kidney injury. Knockout of Rest in renal tubules significantly alleviates AKI and its progression to chronic kidney disease (CKD). These findings highlight the involvement of REST in the transition from AKI to CKD and reveal its ferroptosis-inducing effect, suggesting it as a potential therapeutic target for AKI and CKD.