Hara Satoshi, Kobayashi Namiko, Sakamoto Kazuo, Ueno Toshiharu, Manabe Shun, Takashima Yasutoshi, Hamada Juri, Pastan Ira, Fukamizu Akiyoshi, Matsusaka Taiji, Nagata Michio
Department of Kidney and Vascular Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan; Division of Rheumatology, Department of Internal Medicine, Kanazawa Graduate School of Medicine, Kanazawa, Japan.
Department of Kidney and Vascular Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Am J Pathol. 2015 Aug;185(8):2118-31. doi: 10.1016/j.ajpath.2015.04.007. Epub 2015 Jun 11.
Intracapillary foam cell infiltration with podocyte alterations is a characteristic pathology of focal segmental glomerulosclerosis (FSGS). We investigated the possible role of podocyte injury in glomerular macrophage and foam cell infiltration in a podocyte-selective injury model (NEP25 mice) and hypercholesterolemic model [low-density lipoprotein receptor deficiency (LDLR(-/-)) mice] with doxorubicin-induced nephropathy. Acute podocyte selective injury alone failed to induce glomerular macrophages in the NEP25 mice. However, in the doxorubicin-treated hypercholesterolemic LDLR(-/-) mice, glomerular macrophages/foam cells significantly increased and were accompanied by lipid deposition and the formation and ingestion of oxidized phospholipids (oxPLs). Glomerular macrophages significantly correlated with the amount of glomerular oxPL. The NEP25/LDLR(-/-) mice exhibited severe hypercholesterolemia, glomerular lipid deposition, and renal dysfunction. Imaging mass spectrometry revealed that a major component of oxidized low-density lipoprotein, lysophosphatidylcholine 16:0 and 18:0, was present only in the glomeruli of NEP25/LDLR(-/-) mice. Lysophosphatidylcholine 16:0 stimulated mesangial cells and macrophages, and lysophosphatidylcholine 18:0 stimulated glomerular endothelial cells to express adhesion molecules and chemokines, promoting macrophage adhesion and migration in vitro. In human FSGS, glomerular macrophage-derived foam cells contained oxPLs accompanied by the expression of chemokines in the tuft. In conclusion, glomerular lipid modification represents a novel pathology by podocyte injury, promoting FSGS. Podocyte injury-driven lysophosphatidylcholine de novo accelerated glomerular macrophage-derived foam cell infiltration via lysophosphatidylcholine-mediated expression of adhesion molecules and chemokines in glomerular resident cells.
伴有足细胞改变的毛细血管内泡沫细胞浸润是局灶节段性肾小球硬化（FSGS）的特征性病理表现。我们在足细胞选择性损伤模型（NEP25小鼠）和高胆固醇血症模型[低密度脂蛋白受体缺陷（LDLR(-/-)）小鼠]中，研究了阿霉素诱导的肾病中足细胞损伤在肾小球巨噬细胞和泡沫细胞浸润中的可能作用。单独的急性足细胞选择性损伤未能在NEP25小鼠中诱导肾小球巨噬细胞。然而，在阿霉素处理的高胆固醇血症LDLR(-/-)小鼠中，肾小球巨噬细胞/泡沫细胞显著增加，并伴有脂质沉积以及氧化磷脂（oxPLs）的形成和摄取。肾小球巨噬细胞与肾小球oxPL的量显著相关。NEP25/LDLR(-/-)小鼠表现出严重的高胆固醇血症、肾小球脂质沉积和肾功能障碍。成像质谱显示，氧化低密度脂蛋白的主要成分溶血磷脂酰胆碱16:0和18:0仅存在于NEP25/LDLR(-/-)小鼠的肾小球中。溶血磷脂酰胆碱16:0刺激系膜细胞和巨噬细胞，溶血磷脂酰胆碱18:0刺激肾小球内皮细胞表达黏附分子和趋化因子，促进巨噬细胞在体外的黏附和迁移。在人类FSGS中，肾小球巨噬细胞衍生的泡沫细胞含有oxPLs，并伴有肾小球中趋化因子的表达。总之，肾小球脂质修饰代表了一种由足细胞损伤引起的新病理，促进了FSGS。足细胞损伤驱动的溶血磷脂酰胆碱从头合成通过溶血磷脂酰胆碱介导的肾小球驻留细胞中黏附分子和趋化因子的表达加速了肾小球巨噬细胞衍生的泡沫细胞浸润。
