There are no effective treatments other than supportive care for preventing or halting the development of chronic kidney disease (CKD) after acute kidney injury (AKI), leaving affected patients at high risk of CKD-associated cardiovascular events and mortality. One critical factor that contributes to the AKI-to-CKD transition is oxidative stress-mediated renal epithelial damage, which precludes healthy renal repair. Our data identify tubular epithelial cells undergo excessive lipid peroxidation after renal ischemia-reperfusion, which results in the execution of ferroptosis, a newly identified non-apoptotic regulated cell death. Importantly, pharmacological inhibition of ferroptosis improves the severity of AKI in preclinical models. However, the molecular and cellular mechanisms of ferroptosis in AKI-to-CKD transition are poorly elucidated, hampering the establishment of anti-ferroptosis therapy for this devastating disease condition. To advance this promising and clinically relevant line of investigation, we will test our central hypotheses that: in the setting of the severe tubular oxidative stress in AKI, insufficient tubular activation of anti-ferroptotic defense pathways induces dysfunction and depletion of renal epithelial cells, which precludes healthy healing of injured kidneys and drives the progression of CKD. To test our hypotheses, we will integrate unbiased single-cell transcriptomic, and mouse genetics approaches in following two Specific Aims: (1) Establish ferroptosis in tubular epithelial cells as a key driving mechanism of AKI-to-CKD transition by genetically deleting the anti-ferroptotic defense enzyme, glutathione peroxidase 4 (GPX4), from the renal tubular epithelial cells.; and (2) Investigate molecular mechanisms underlying ferroptosis at a single-cell resolution. In summary, we expect to elucidate the fundamental roles of ferroptosis in the AKI-to-CKD transition. Our results will lay the scientific foundation for targeting anti-ferroptotic pathways to enhance renal repair/regeneration as a novel therapy to prevent the AKI-to-CKD transition. This proposed research will propel me towards my long-term research goal of contributing to forming the scientific basis of future clinical trials to test anti-oxidative stress and anti-ferroptosis pathways for the prevention of this devastating disease process.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|