Lin Yujiao, Yuan Ying, Ye Keng, Chen Zhimin, Wang Yujia, Li Guoping, Song Yankun, Chen Hong, Ma Huabin, Xu Yanfang
Department of Nephrology, Blood Purification Research Center, First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
Research Center for Metabolic Chronic Kidney Disease, First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
Nephrol Dial Transplant. 2025 Apr 28;40(5):943-955. doi: 10.1093/ndt/gfae226.
Oxalate nephropathy is characterized by calcium oxalate crystals deposition, which triggers necrosis of renal tubular epithelial cells and initiates an inflammatory cascade characterized by neutrophil and macrophage activation within the renal microenvironment. Despite the close association of immune cells with acute oxalate nephropathy, the underlying mechanisms still remain unclear. Nerve injury-induced protein 1 (NINJ1) plays an essential role in the induction of plasma membrane rupture (PMR), leading to damage-associated molecular patterns (DAMPs) release and triggering inflammation. We hypothesize that NINJ1-mediated high mobility group box 1 (HMGB1) release from macrophage PMR and neutrophil extracellular traps (NETs) formation synergistically contribute to the progression of acute oxalate nephropathy.
Using a murine model of acute oxalate nephropathy, myeloid cell-specific deletion of Ninj1 mice (Ninj1fl/flvavcre) and their wild-type littermate control mice (Ninj1wt/wtvavcre) were administered intraperitoneal injection of 100 mg/kg sodium oxalate followed by drinking water with 3% sodium oxalate. Evaluation was conducted on tubular injury and inflammatory cell infiltration. In vitro studies involved isolation and culture of renal proximal tubular epithelial cells, bone marrow-derived macrophages and neutrophils to investigate NETs formation and HMGB1 release.
Targeted deletion of Ninj1 in myeloid cells significantly mitigated oxalate-induced acute kidney injury by suppressing both HMGB1 release and NETs formation in vivo. In vitro investigations demonstrated that HMGB1 release from macrophage PMR and NETs formation in neutrophils mediated by NINJ1 oligomerization, which consequently coordinated to enhance renal tubular epithelial cell death.
Our findings elucidate the pivotal role of NINJ1-dependent macrophage PMR and NETs formation in the progression of acute oxalate nephropathy, providing novel insights for its prevention and therapeutic targets.
草酸肾病的特征是草酸钙晶体沉积，这会引发肾小管上皮细胞坏死，并在肾脏微环境中启动以中性粒细胞和巨噬细胞激活为特征的炎症级联反应。尽管免疫细胞与急性草酸肾病密切相关，但其潜在机制仍不清楚。神经损伤诱导蛋白1（NINJ1）在诱导质膜破裂（PMR）中起重要作用，导致损伤相关分子模式（DAMPs）释放并引发炎症。我们假设NINJ1介导的巨噬细胞PMR释放高迁移率族蛋白B1（HMGB1）和中性粒细胞胞外陷阱（NETs）形成协同促进急性草酸肾病的进展。
使用急性草酸肾病小鼠模型，对髓系细胞特异性缺失Ninj1的小鼠（Ninj1fl/flvavcre）及其野生型同窝对照小鼠（Ninj1wt/wtvavcre）腹腔注射100 mg/kg草酸钠，随后饮用含3%草酸钠的水。对肾小管损伤和炎症细胞浸润进行评估。体外研究包括分离和培养肾近端小管上皮细胞、骨髓来源的巨噬细胞和中性粒细胞，以研究NETs形成和HMGB1释放。
髓系细胞中Ninj1的靶向缺失通过抑制体内HMGB1释放和NETs形成，显著减轻了草酸盐诱导的急性肾损伤。体外研究表明，NINJ1寡聚化介导巨噬细胞PMR释放HMGB1和中性粒细胞形成NETs，从而协同增强肾小管上皮细胞死亡。
我们的研究结果阐明了NINJ1依赖性巨噬细胞PMR和NETs形成在急性草酸肾病进展中的关键作用，为其预防和治疗靶点提供了新的见解。
