Xu Xiaoying, Gou Linfeng, Zhou Meng, Yang Fusheng, Zhao Yihan, Feng Tingting, Shi Peikun, Ghavamian Armin, Zhao Weiming, Yu Yuan, Lu Yi, Yi Fan, Liu Guangyi, Tang Wei
Department of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong, PR China.
Department of Pharmacology, Shandong University School of Medicine, Jinan, Shandong, PR China.
Int Immunopharmacol. 2016 Sep;38:409-19. doi: 10.1016/j.intimp.2016.06.022. Epub 2016 Jun 29.
Progranulin (PGRN), a pluripotent secreted growth factor, is involved in various physiologic and disease processes. However, the role of PGRN in endotoxin-induced septic acute kidney injury (AKI) remains unknown. The objective of this study is to investigate the protective effects of PGRN on an endotoxin-induced AKI mouse model by using PGRN-deficient mice and recombinant PGRN (rPGRN) pretreatment. PGRN levels were increased in kidneys of wild-type (WT) mice at 6 and 24h after lipopolysaccharide (LPS) injection. Renal function detection, hematoxylin and eosin staining, immunohistochemical staining, ELISA and in situ terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick-end labeling were used to reveal tissue injury, inflammatory cell infiltration, production of inflammatory mediators and cell death in mouse kidneys after LPS injection. PGRN deficiency resulted in severe kidney injury and increased apoptotic death, inflammatory cell infiltration, production of pro-inflammatory mediators and the expression and nucleus-to-cytoplasmic translocation of HMGB1 in the kidney. In addition, rPGRN administration before LPS treatment ameliorated the endotoxin-induced AKI in WT mice. PGRN may be a novel biologic agent with therapeutic potential for endotoxin-induced septic AKI possibly by inhibiting LPS-induced renal cell death and inflammatory responses in mice.
颗粒蛋白前体（PGRN）是一种多能分泌性生长因子，参与多种生理和疾病过程。然而，PGRN在内毒素诱导的脓毒症急性肾损伤（AKI）中的作用尚不清楚。本研究的目的是通过使用PGRN基因敲除小鼠和重组PGRN（rPGRN）预处理，研究PGRN对在内毒素诱导的AKI小鼠模型中的保护作用。脂多糖（LPS）注射后6小时和24小时，野生型（WT）小鼠肾脏中的PGRN水平升高。采用肾功能检测、苏木精-伊红染色、免疫组织化学染色、ELISA和原位末端脱氧核苷酸转移酶介导的尿苷三磷酸缺口末端标记法，揭示LPS注射后小鼠肾脏中的组织损伤、炎性细胞浸润、炎性介质产生和细胞死亡情况。PGRN缺乏导致严重的肾损伤，并增加凋亡性死亡、炎性细胞浸润、促炎介质产生以及肾脏中高迁移率族蛋白B1（HMGB1）的表达和核转位。此外，在LPS处理前给予rPGRN可改善WT小鼠的内毒素诱导的AKI。PGRN可能是一种具有治疗潜力的新型生物制剂，其对内毒素诱导的脓毒症AKI的治疗作用可能是通过抑制LPS诱导的小鼠肾细胞死亡和炎症反应来实现的。
