lncRNA-gm33782 exacerbates renal inflammation and injury in AKI by activating M1 macrophage polarization through Ccl5/NF-κB signaling.

Acute kidney injury (AKI) progression is closely linked to dysregulated macrophage activation, but the role of tubular-derived lncRNAs in modulating macrophage-driven inflammation remains poorly understood. Here, we identified ‌lncRNA-gm33782‌ as a potentially pathogenic mediator in AKI due to its strongly upregulated expression in ischemia-reperfusion injury (IRI) and cisplatin (Cis) induced AKI mouse models. Interestingly, in Cis-AKI model, renal-specific knockdown of ‌lncRNA-gm33782 via in vivo electroporation significantly attenuated tubular injury and macrophage infiltration. RNA-seq of ‌lncRNA-gm33782 overexpressed tubular epithelial cells (TECs) revealed ‌Ccl5‌ as the top upregulated chemokine, while protein-protein interaction (PPI) analysis linked Ccl5 to NF-κB activation. Mechanistically, conditioned media from ‌lncRNA-gm33782-overexpressed TECs promoted pro-inflammatory responses in bone marrow-derived macrophages (BMDMs), whereas silencing Ccl5 in TECs attenuated macrophage inflammation. Notably, co-culture of lncRNA-gm33782 overexpressed TECs with BMDMs exacerbated both macrophage M1 polarization and tubular injury marker - Tim-1, establishing a feedforward loop of renal damage. Rescue experiments demonstrated that simultaneous overexpression of lncRNA-gm33782 and knockdown of Ccl5 reversed macrophage-driven inflammation and tubular injury, indicating that Ccl5 serves as the key effector for lncRNA-gm33782-mediated macrophage inflammation and its feedback-driven tubular injury. These findings reveal that tubular-derived lncRNA-gm33782 drives AKI progression by activating the Ccl5/NF-κB pathway to promote M1 macrophage polarization, highlighting lncRNA-gm33782 as a potential therapeutic target for immune modulation in AKI.