PGRN acts as a novel regulator of mitochondrial homeostasis by facilitating mitophagy and mitochondrial biogenesis to prevent podocyte injury in diabetic nephropathy
PGRN acts as a novel regulator of mitochondrial homeostasis by facilitating mitophagy and mitochondrial biogenesis to prevent podocyte injury in diabetic nephropathy
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PGRN 通过促进线粒体自噬和线粒体生物发生来充当线粒体稳态的新型调节剂，以预防糖尿病肾病的足细胞损伤
DOI：
10.1038/s41419-019-1754-3
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发表时间：
2019-07-08
影响因子：
9
通讯作者：
Yi, Fan
中科院分区：
文献类型：
--
作者：
Zhou, Di;Zhou, Meng;Yi, Fan
线粒体功能障碍被认为是糖尿病肾病（DN）发病的关键中介。针对线粒体功能障碍的治疗策略对DN的治疗具有相当大的希望。在这项研究中，我们研究了前颗粒蛋白（PGRN），一种分泌糖蛋白，在介导线粒体稳态中的作用及其在DN中的治疗潜力。我们发现，与健康对照相比，stz诱导的糖尿病小鼠和活检证实的DN患者肾脏中的PGRN水平显著降低。在DN模型中，pgrn缺陷小鼠与野生型小鼠相比，足细胞损伤和蛋白尿加重。功能上，PGRN缺乏加重了糖尿病小鼠足细胞的线粒体损伤和功能障碍。在体外，用重组人PGRN （rPGRN）处理可减轻高糖诱导的足细胞线粒体功能障碍，同时增强线粒体生物发生和线粒体自噬。线粒体自噬的抑制干扰了PGRN对高糖诱导足细胞毒性的保护作用。在机制上，我们证明了PGRN通过PGRN- sirt1 - pgc -1α/FoxO1信号介导的线粒体生物发生和线粒体自噬来维持线粒体稳态。最后，我们为PGRN对DN小鼠的治疗潜力提供了直接证据。这项研究为PGRN在维持线粒体稳态中的新作用提供了新的见解，表明PGRN可能是治疗DN患者的一种创新治疗策略。
Mitochondrial dysfunction is considered as a key mediator in the pathogenesis of diabetic nephropathy (DN). Therapeutic strategies targeting mitochondrial dysfunction hold considerable promise for the treatment of DN. In this study, we investigated the role of progranulin (PGRN), a secreted glycoprotein, in mediating mitochondrial homeostasis and its therapeutic potential in DN. We found that the level of PGRN was significantly reduced in the kidney from STZ-induced diabetic mice and patients with biopsy-proven DN compared with healthy controls. In DN model, PGRN-deficient mice aggravated podocyte injury and proteinuria versus wild-type mice. Functionally, PGRN deficiency exacerbated mitochondrial damage and dysfunction in podocytes from diabetic mice. In vitro, treatment with recombinant human PGRN (rPGRN) attenuated high glucose-induced mitochondrial dysfunction in podocytes accompanied by enhanced mitochondrial biogenesis and mitophagy. Inhibition of mitophagy disturbed the protective effects of PGRN in high glucose-induced podocytotoxicity. Mechanistically, we demonstrated that PGRN maintained mitochondrial homeostasis via PGRN-Sirt1-PGC-1α/FoxO1 signaling-mediated mitochondrial biogenesis and mitophagy. Finally, we provided direct evidence for therapeutic potential of PGRN in mice with DN. This study provides new insights into the novel role of PGRN in maintaining mitochondrial homeostasis, suggesting that PGRN may be an innovative therapeutic strategy for treating patients with DN.