The NF-κB/miR-378c/IRG1 axis drives tubular injury in septic AKI by suppressing immunometabolic protection

Abstract

Septic acute kidney injury (AKI) is a life-threatening complication with high morbidity and mortality. Despite decades of research, therapeutic options remain limited to supportive care, underscoring the urgent need to decipher the molecular drivers that govern septic AKI. We used a murine LPS-induced septic AKI model and cultured BUMPT cells. miR-378c expression was assessed by qPCR and fluorescence in situ hybridization. Gain- and loss-of-function studies were performed using miR-378c mimics or locked nucleic acid (LNA) inhibitors in vivo and immune-responsive gene 1 (IRG1) overexpression in vitro. Molecular mechanisms were investigated via chromatin immunoprecipitation (ChIP), luciferase reporter assays, western blotting, and immunofluorescence. miR-378c was significantly upregulated in renal proximal tubules after LPS challenge. NF-κB p65 directly bound to the miR-378c host gene promoter and drove its transcription, confirmed by ChIP and NF-κB inhibition with TPCA-1. Overexpression of miR-378c exacerbated kidney dysfunction, tubular apoptosis, and inflammation, while its inhibition conferred protection. IRG1, encoding the immunomodulatory enzyme that produces itaconate, was identified as a direct target of miR-378c. miR-378c suppressed IRG1 expression, and IRG1 overexpression alone reduced LPS-induced apoptosis and proinflammatory cytokine production (IL-1β, IL-6, TNF-α). We define a maladaptive NF-κB/miR-378c/IRG1 axis in septic AKI, where inflammation-induced miR-378c silences a key metabolic protector in tubular cells. Targeting this pathway represents a promising therapeutic strategy to preserve renal function during sepsis.