Progranulin protects against renal ischemia/reperfusion injury in mice

Progranulin (PGRN), an autocrine growth factor, has multiple physiological functions and is widely involved in the pathogenesis of many types of diseases. The pivotal anti-inflammatory function of PGRN in rheumatoid arthritis encouraged us to examine the role of PGRN in acute kidney injury (AKI). We found that levels of PGRN were significantly reduced in the kidney in a mouse model of renal ischemia/ reperfusion injury. We also observed that PGRN deficiency (Grn(-/)- mice) significantly aggravated renal injury as evidenced by higher serum creatinine, more severe morphological injury, increased tubular epithelial cell death, and tubulointerstitial neutrophil and macrophage infiltration versus wild-type mice. In vitro, we found that recombinant human PGRN attenuated hypoxia-induced inflammatory actions and apoptosis in proximal tubule epithelial cells, at least in part associated with a nucleotide-binding oligomerization domain containing 2 (NOD2)-mediated immune response. Importantly, pretreatment with or delayed administration of recombinant human PGRN protected against or promoted recovery from renal ischemia/reperfusion injury in wild-type and Grn(-/-) mice. Similar protective effects were also found in cisplatin-induced AKI. Thus, our findings provide a better understanding of the biological activities of PGRN in the kidney and suggest that PGRN may be an innovative therapeutic strategy for treating patients with AKI.

颗粒蛋白前体（PGRN）是一种自分泌生长因子，具有多种生理功能，并广泛参与多种疾病的发病机制。PGRN在类风湿关节炎中关键的抗炎功能促使我们研究其在急性肾损伤（AKI）中的作用。我们发现，在肾缺血/再灌注损伤的小鼠模型中，肾脏中PGRN的水平显著降低。我们还观察到，与野生型小鼠相比，PGRN缺乏（Grn（ - / - ）小鼠）显著加重了肾损伤，表现为血清肌酐更高、形态学损伤更严重、肾小管上皮细胞死亡增加以及肾小管间质中性粒细胞和巨噬细胞浸润。在体外，我们发现重组人PGRN减轻了近端肾小管上皮细胞中缺氧诱导的炎症反应和细胞凋亡，这至少部分与含核苷酸结合寡聚化结构域2（NOD2）介导的免疫反应有关。重要的是，重组人PGRN预处理或延迟给药可保护野生型和Grn（ - / - ）小鼠免受肾缺血/再灌注损伤，或促进其从该损伤中恢复。在顺铂诱导的AKI中也发现了类似的保护作用。因此，我们的研究结果使人们更好地理解了PGRN在肾脏中的生物学活性，并表明PGRN可能是治疗AKI患者的一种创新治疗策略。