Roxadustat protects against renal ischemia-reperfusion injury in mice but upregulates NKG2D ligands (MICA in human cells, RAE-1/H60 in mice), warranting further study of its mechanisms and consequences in AKI and post-renal transplantation.
MICA expression was elevated in kidney tissue from patients with acute kidney injury (AKI) or post-renal transplantation (PRT) compared with controls.
Roxadustat (FG-4592) pretreatment attenuated renal ischemia-reperfusion injury-induced kidney dysfunction and tubular injury in mice.
FG-4592 stabilized HIF-1α protein levels in the mouse kidney during renal IRI.
FG-4592 enhanced expression of murine NKG2D ligands (RAE-1 and H60) at both transcriptional and translational levels in renal IRI.
Hypoxia/reoxygenation upregulated MICA in human tubular cells and RAE-1 in mouse tubular cells, and FG-4592 potentiated this response in vitro.
The authors conclude that Roxadustat protects against renal IRI but upregulates NKG2D ligands, and that mechanisms and consequences in AKI/PRT need further study.
This study looked at roxadustat, a drug that makes cells respond as though oxygen is low by stabilizing a protein called HIF. Roxadustat has been reported to protect the kidneys. The researchers examined what it does in kidney injury caused by a temporary loss of blood flow followed by its return (ischemia-reperfusion injury), a common cause of acute kidney injury and of problems in transplanted kidneys. They focused on NKG2D ligands, stress molecules on cells that can activate immune cells. In humans the main one is MICA, and in mice they are RAE-1 and H60. In kidney biopsies, patients with acute kidney injury or a transplanted kidney had more MICA than controls. In mice, roxadustat given before injury reduced kidney dysfunction and damage to the kidney tubules, and it stabilized HIF-1α. However, it also increased the levels of the immune-activating ligands RAE-1 and H60. Experiments in human and mouse kidney tubular cells exposed to low oxygen followed by reoxygenation showed the same pattern: the stress raised MICA or RAE-1, and roxadustat increased this further. This research suggests roxadustat may protect kidney tissue while also boosting signals that could draw in immune cells. It is unclear whether that increase helps, harms, or has no effect on outcomes, especially in transplant patients, where immune activity matters. The findings come from mice and cell cultures plus patient biopsies, so more work is needed to understand the mechanisms and the real-world consequences.
Yang H, Xu N, Wu Y, Cheng M, Qiu X, Liu S, et al.. (2026). Roxadustat (FG-4592) Attenuates Renal Ischemia-Reperfusion Injury but Upregulates the NKG2D Ligand MICA.. Biomolecules. https://doi.org/10.3390/biom16101437