Abstract: TH-PO0655
Ferroptotic Injury Drives Two Distinct Proximal Tubule Cell Fate Trajectories During Maladaptive Kidney Repair
Session Information
- AKI: Mechanisms - Inflammation and Repair
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Kitai, Hiroki, Duke University School of Medicine, Durham, North Carolina, United States
- Abe, Koki, Duke University School of Medicine, Durham, North Carolina, United States
- Enya, Takuji, Duke University School of Medicine, Durham, North Carolina, United States
- Ito, Ryo, Duke University School of Medicine, Durham, North Carolina, United States
- Chang, Fan-Chi, Duke University School of Medicine, Durham, United States
- Souma, Tomokazu, Duke University School of Medicine, Durham, North Carolina, United States
Background
Acute kidney injury (AKI) is a major health problem, afflicting 1.2 million hospitalized patients annually in the US alone. Maladaptive renal repair after AKI promotes the development of chronic kidney disease (CKD), leaving affected patients at high risk for dialysis dependency, cardiovascular events, and mortality. Thus, we urgently need new therapeutic approaches to improve kidney repair after AKI. One critical pathway that is implicated in AKI pathogenesis is ferroptosis, an iron-dependent, lipid-peroxidation-driven, regulated cell death. Glutathione peroxidase 4 (GPX4) acts as the central defense enzyme that prevents ferroptosis, and global genetic deletion of GPX4 causes early lethality due to proximal tubule cell death. However, the effects of GPX4 insufficiency in maladaptive repair after AKI are poorly understood, and its effects beyond cell death in proximal tubule cells are unclear.
Methods
We employed single-cell transcriptomics and mouse genetics to determine the effects of Gpx4 insufficiency in renal tubule epithelial cells in mice in vivo. We used a mouse line that enables selective deletion of Gpx4 in renal tubular epithelial cells in a doxycycline-inducible manner (Pax8rtTA; tetOCre; Gpx4 flox/flox).
Results
Doxycycline feeding selectively and efficiently induced tubular Gpx4 deletion, which triggered robust cell death acutely on days 10 and 14, particularly in male mice. To our surprise, these Gpx4-deleted mice escaped the lethality seen in global knockout mice and survived at least 6 months after tubular Gpx4 deletion. The Gpx4-deleted kidneys exhibited a severe CKD phenotype, characterized by fibrosis and chronic inflammation. We also found that many Gpx4-deficient proximal tubule cells escaped ferroptotic cell death and accumulated in the injured kidneys. Our single-cell transcriptomics analyses identified that these ferroptosis-surviving proximal tubule cells were transcriptionally reprogrammed into an inflammatory, dedifferentiated cell state, characterized by the expression of Sox9 and Vcam1 genes. These survivors potentially create a feedforward proinflammatory loop with infiltrating immune cell populations, thereby driving fibrosis.
Conclusion
In summary, our findings show that ferroptotic injury not only induces cell death but also reprograms surviving cells into maladaptive, failed-repair, proinflammatory proximal tubule states.
Funding
- NIDDK Support