Augmenter of liver regeneration (ALR) can regulate iron homeostasis through the INOS/NO/SLC39A14 pathway to reduce ferroptosis in acute kidney injury.

Abstract

Acute kidney injury (AKI) is a complex clinical syndrome that affects approximately 13.3 million people worldwide each year. Although ferroptosis has been implicated in the pathological progression of AKI, the underlying mechanisms remain elusive. Augmenter of liver regeneration (ALR) plays a role in apoptosis, autophagy and oxidative stress induction in renal tubular epithelial cells; however, the specific mechanisms through which ALR is involved in AKI are unclear. The present study investigated the effects of ALR on regulating iron uptake and ferroptosis in AKI under in vivo and in vitro conditions. Renal tubular epithelial cell-specific Alr knockout (AlrKO) mice and ischaemia/reperfusion (I/R)-induced AKI in vivo models were generated. ALR overexpression and hypoxia/reoxygenation (H/R)-induced AKI in vitro models were generated using human renal tubular epithelial cells. The effects of ALR on ferroptosis and kidney function in AKI were investigated through in vitro and in vivo studies involving biochemical analysis, RT-qPCR, western blotting assay, immunofluorescence assay, and transmission electron microscopy. Transcriptome sequencing, iron homeostasis, and inducible nitric oxide synthase (iNOS)/nitric oxide (NO) synthesis detection were performed to investigate the mechanisms through which ALR affects AKI. Loss-of-function experiments revealed that kidney tubule-specific Alr knockout in mice exacerbated iron uptake, ferroptosis, and acute kidney I/R injury. Mechanistically, we found that ALR could regulate iron homeostasis through the iNOS/NO/Solute carrier family 39 member 14 (SLC39A14) pathway to reduce ferroptosis in AKI. The results of this study reveal a previously undescribed function of ALR in iron homeostasis and ferroptosis in AKI, and suggest that targeting ALR could be a potential treatment option for AKI.