Department of Nephrology, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Sci Rep. 2021 Jan 13;11(1):1194. doi: 10.1038/s41598-020-80940-8.
Progranulin (PGRN) has been reported to bind tumor necrosis factor (TNF) receptor and to inhibit TNFα signaling. We evaluated the effect of augmentation of TNFα signaling by PGRN deficiency on the progression of kidney injury. Eight-week-old PGRN knockout (KO) and wild-type (WT) mice were fed a standard diet or high-fat diet (HFD) for 12 weeks. Albuminuria, markers of tubular damage, and renal mRNA levels of inflammatory cytokines were higher in HFD-fed KO (KO-HFD) mice than in HFD-fed WT (WT-HFD) mice. Body weight, vacuolization in proximal tubules, and systemic and adipose tissue inflammatory markers were lower in the KO-HFD mice than in the WT-HFD mice. The renal megalin expression was lower in the KO mice than in the WT mice regardless of the diet type. The megalin expression was also reduced in mouse proximal tubule epithelial cells stimulated with TNFα and in those with PGRN knockdown by small interfering RNA in vitro. PGRN deficiency was associated with both exacerbated renal inflammation and decreased systemic inflammation, including that in the adipose tissue of mice with HFD-induced obesity. Improved tubular vacuolization in the KO-HFD mice might partially be explained by the decreased expression of megalin in proximal tubules.
颗粒体蛋白聚糖（PGRN）已被报道可与肿瘤坏死因子（TNF）受体结合，并抑制 TNFα 信号通路。我们评估了 PGRN 缺乏对肾脏损伤进展的 TNFα 信号通路增强的影响。将 8 周龄的 PGRN 敲除（KO）和野生型（WT）小鼠分别用标准饮食或高脂肪饮食（HFD）喂养 12 周。与 HFD 喂养的 WT（WT-HFD）小鼠相比，HFD 喂养的 KO（KO-HFD）小鼠的蛋白尿、肾小管损伤标志物和肾脏炎性细胞因子 mRNA 水平更高。KO-HFD 小鼠的体重、近端肾小管空泡化以及全身和脂肪组织炎症标志物均低于 WT-HFD 小鼠。无论饮食类型如何，KO 小鼠的肾脏 megalin 表达均低于 WT 小鼠。在体外，用 TNFα 刺激的小鼠近端肾小管上皮细胞和用小干扰 RNA 敲低 PGRN 的细胞中，megalin 的表达也减少。PGRN 缺乏与肥胖症诱导的 HFD 小鼠的肾脏炎症加重和全身炎症（包括脂肪组织炎症）减少均有关。KO-HFD 小鼠的肾小管空泡化改善可能部分归因于近端肾小管中 megalin 表达减少。
