Tan Rui-Zhi, Li Tong, Jia Jian, Wang Rui, Lin Jing-Yi, Kantawong Fahsai, Wang Li
Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; Research Center of Intergated Traditional Chinese and Western Medicine, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou 646000, China.
Research Center of Intergated Traditional Chinese and Western Medicine, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China.
Int Immunopharmacol. 2025 Aug 28;161:115087. doi: 10.1016/j.intimp.2025.115087. Epub 2025 Jun 16.
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.
急性肾损伤（AKI）的进展与巨噬细胞活化失调密切相关，但肾小管来源的长链非编码RNA（lncRNA）在调节巨噬细胞驱动的炎症中的作用仍知之甚少。在此，我们鉴定出lncRNA-gm33782是AKI中一种潜在的致病介质，因为它在缺血再灌注损伤（IRI）和顺铂（Cis）诱导的AKI小鼠模型中表达强烈上调。有趣的是，在Cis-AKI模型中，通过体内电穿孔对lncRNA-gm33782进行肾脏特异性敲低可显著减轻肾小管损伤和巨噬细胞浸润。对lncRNA-gm33782过表达的肾小管上皮细胞（TECs）进行RNA测序显示Ccl5是上调最明显的趋化因子，而蛋白质-蛋白质相互作用（PPI）分析将Ccl5与NF-κB激活联系起来。机制上，lncRNA-gm33782过表达的TECs的条件培养基促进了骨髓来源巨噬细胞（BMDMs）中的促炎反应，而在TECs中沉默Ccl5可减轻巨噬细胞炎症。值得注意的是，lncRNA-gm33782过表达的TECs与BMDMs共培养加剧了巨噬细胞M1极化和肾小管损伤标志物Tim-1，建立了肾脏损伤的前馈回路。挽救实验表明，同时过表达lncRNA-gm33782和敲低Ccl5可逆转巨噬细胞驱动的炎症和肾小管损伤，表明Ccl5是lncRNA-gm33782介导的巨噬细胞炎症及其反馈驱动的肾小管损伤的关键效应因子。这些发现揭示，肾小管来源的lncRNA-gm33782通过激活Ccl5/NF-κB途径促进M1巨噬细胞极化来驱动AKI进展，突出了lncRNA-gm33782作为AKI免疫调节潜在治疗靶点的作用。
