IER3 drives the transition from sepsis-associated AKI to CKD by suppressing the mitochondrial translocation of PRDX5

Sepsis-associated acute kidney injury (SAKI) is a severe condition associated with high mortality and long-term complications. Currently, there is no effective strategy to halt AKI chronicization. Stress-induced senescence of renal tubular epithelial cells (RTECs) is a pivotal driving mechanism in the AKI-CKD transition. Previous scRNA-seq revealed that the expression of immediate early response gene 3 (IER3) was markedly upregulated in the senescent RTECs of patients with AKI and that the IER3⁺RTEC subpopulation exhibited diminished differentiation potential and impaired self-renewal capacity. However, the role of IER3 in RTEC stress-induced senescence following AKI remains unclear. In this study, we found that knockout of IER3 reduced mortality rates, alleviated renal injury, mitigated renal maladaptive fibrotic repair, and concurrently inhibited RTEC stress-induced senescence after SAKI. Further RNA-seq of IER3^-/- mouse renal tissues revealed significant upregulation of peroxiredoxin 5 (PRDX5) in the absence of IER3. Inhibition of PRDX5 blocked the effects of IER3 knockout on RTEC stress-induced senescence under septic conditions. Intriguingly, we found that IER3 interacted with the presenilin-associated rhomboid-like gene (Parl) and reduced its shear activity. This interaction also inhibited the cleavage and subsequent mitochondrial translocation of cytoplasmic PRDX5, leading to decreased mitochondrial levels in PRDX5 and impaired antioxidant capacity. These changes resulted in oxidative mitochondrial damage and abnormal perinuclear clustering of mitochondria, which promote stress-induced cellular senescence and ultimately facilitates the transition from AKI to CKD. In conclusion, our findings suggest that IER3 might induce RTEC senescence and exacerbate the AKI-CKD transition in sepsis-associated AKI by inhibiting mitochondrial translocation of PRDX5.