FN3K alleviates renal ischemia-reperfusion injury by regulating oxidative stress through Nrf2 deglycation.

Abstract

Renal ischemia-reperfusion injury (RIRI) is a common cause of acute kidney injury in clinical practice, frequently occurring in renal transplantation, partial nephrectomy, and cardiac surgery. Similar to phosphorylation and ubiquitination, glycation is a form of post-translational modification that is widely present in mammals. However, glycation/deglycation has not yet been investigated in the context of RIRI. To explore its regulatory role in acute-phase RIRI, we established both in vivo and in vitro renal ischemia-reperfusion models and examined the protective mechanism of the deglycating enzyme fructosamine-3-kinase (FN3K). Our results demonstrated that FN3K expression was markedly down-regulated following RIRI. FN3K over-expression alleviated renal injury in mice and cells, primarily by reducing oxidative stress and apoptosis, whereas FN3K knockdown exerted the opposite effects. Mechanistically, the protective role of FN3K was dependent on Nrf2. Specifically, FN3K promoted the nuclear translocation and antioxidant activity of Nrf2 by mediating its deglycation. In conclusion, this study is the first to reveal that FN3K confers protection against RIRI by regulating Nrf2 deglycation, thereby broadening our understanding of oxidative stress mechanisms underlying ischemia-reperfusion-induced acute kidney injury. Furthermore, these findings provide a novel theoretical basis for targeting the FN3K-Nrf2 signaling axis, and highlight a potential therapeutic target for precision intervention in acute kidney injury and the prevention of post-transplant complications.