Progranulin alleviates podocyte injury via regulating CAMKK/AMPK-mediated autophagy under diabetic conditions
Progranulin alleviates podocyte injury via regulating CAMKK/AMPK-mediated autophagy under diabetic conditions
复制标题
颗粒体蛋白前体通过调节糖尿病条件下 CAMKK/AMPK 介导的自噬减轻足细胞损伤
DOI：
10.1007/s00109-019-01828-3
复制
发表时间：
2019-11-01
影响因子：
4.7
通讯作者：
Yi, Fan
中科院分区：
文献类型：
--
作者：
Zhou, Di;Zhou, Meng;Yi, Fan
足细胞损伤被认为是糖尿病肾病（DN）发生的主要原因。因此，鉴定用于预防足细胞损伤的潜在治疗靶点具有临床重要性。最近的研究表明，自噬是维持足细胞完整性和功能的关键稳态机制。本研究旨在阐明颗粒蛋白前体（PGRN）在糖尿病足细胞自噬过程和足细胞损伤中的作用。在高糖（HG）条件下，PGRN在糖尿病小鼠的肾脏和足细胞中下调。PGRN缺乏可加重肾功能损害和肾小球结构改变。在体外，用重组人PGRN（rPGRN）治疗减弱了HG诱导的足细胞损伤，伴随着增强的自噬。自噬的抑制干扰PGRN在HG诱导的足细胞毒性中的保护作用。此外，PGRN通过PGRN-CAMKK-AMPK途径诱导自噬。总的来说，我们的数据证实了PGRN通过恢复自噬和激活CAMKK-AMPK通路在足细胞损伤中的保护作用，这可能为糖尿病肾病的新治疗方式铺平道路。关键信息·糖尿病小鼠肾脏和高糖处理足细胞中PGRN水平降低。·PGRN缺乏会加重糖尿病小鼠的肾损伤PGRN可防止高糖诱导的足细胞损伤。PGRN恢复足细胞中高糖抑制的自噬。PGRN在足细胞损伤中的保护作用需要CAMKK-AMPK通路。
AbstractPodocyte injury is considered a major contributor to the development of diabetic nephropathy (DN). Therefore, identification of potential therapeutic targets for preventing podocyte injury has clinical importance. Recent studies have indicated that autophagy is a key homeostatic mechanism to maintaining podocyte integrity and function. This study was to elucidate the role of progranulin (PGRN), a secreted glycoprotein, in the modulation of podocyte autophagic process and podocyte injury under a diabetic condition. PGRN was downregulated in the kidney from diabetic mice and podocytes under a high-glucose (HG) condition. PGRN deficiency exacerbated the renal dysfunction and glomerular structural alterations. In vitro, treatment with recombinant human PGRN (rPGRN) attenuated HG-induced podocyte injury accompanied by enhanced autophagy. Inhibition of autophagy disturbed the protective effects of PGRN in HG-induced podocytotoxicity. Furthermore, PGRN induced autophagy via the PGRN-CAMKK-AMPK pathway. Collectively, our data identified the protective role of PGRN in podocyte injury via restoring autophagy and activating the CAMKK-AMPK pathway, which may pave the road to new therapeutic modalities for the treatment of diabetic nephropathy.Key messages• PGRN level is reduced in kidney of diabetic mice and high-glucose–treated podocytes.• PGRN deficiency exacerbates renal injury in diabetic mice.• PGRN protects against high-glucose–induced podocyte injury.• PGRN restores high-glucose–inhibited autophagy in podocytes.• CAMKK-AMPK pathway is required for the protective role of PGRN in podocyte injury.