Abstract / Summary
Ischemia–reperfusion injury (IRI) causes acute kidney injury (AKI) and transplant dysfunction. NKG2D ligands (human MICA and murine RAE-1/H60) drive immune activation, while Roxadustat (FG-4592) is reportedly renoprotective. We hypothesized that Roxadustat modulates these ligands in renal IRI. MICA expression was assessed in biopsies from AKI and post-renal transplantation (PRT) patients versus controls. Male Balb/c mice received Roxadustat or vehicle before unilateral IRI, followed by assessment of kidney injury and HIF-1α, RAE-1, and H60 expression. In vitro, human and murine tubular cells underwent hypoxia/reoxygenation with or without FG-4592 pretreatment, and ligand expression was analyzed. Our results showed that MICA expression was elevated in kidney tissues from individuals with AKI or PRT compared with controls. In mice, FG-4592 pretreatment attenuated renal IRI-induced dysfunction and tubular injury, concurrently stabilizing HIF-1α protein levels. Notably, FG-4592 treatment enhanced the expression of murine NKG2D ligands at the transcriptional and translational levels in renal IRI. This effect was corroborated in vitro, where hypoxia/reoxygenation upregulated MICA in human and RAE-1 in mouse tubular cells, a response potentiated by FG-4592. In conclusion, Roxadustat protects against renal IRI but upregulates NKG2D ligands, warranting further study of its mechanisms and consequences in AKI/PRT.