HGF alleviates high glucose-induced injury in podocytes by GSK3 beta inhibition and autophagy restoration
HGF alleviates high glucose-induced injury in podocytes by GSK3 beta inhibition and autophagy restoration
复制标题
HGF 通过 GSK3 β 抑制和自噬恢复减轻高糖诱导的足细胞损伤
DOI：
10.1016/j.bbamcr.2016.08.004
复制
发表时间：
2016
影响因子：
5.1
通讯作者：
Li Hui
中科院分区：
文献类型：
--
作者：
Zhang Congying;Hou Bo;Yu Siying;Chen Qi;Zhang Nong;Li Hui
足细胞损伤或丢失在包括糖尿病肾病（DN）在内的蛋白尿性肾病的发病机制中起主要作用。高基础水平的自噬对足细胞健康至关重要。最近的研究表明肝细胞生长因子（HGF）可以改善足细胞损伤和蛋白尿。然而，关于HGF对足细胞自噬的影响知之甚少。在这项研究中，我们研究了HGF是否以及如何影响高糖（HG）条件下处理的足细胞自噬。HGF能显著减轻HG引起的足细胞凋亡、氧化应激和自噬损伤。一旦HGF受体被c-Met的特异性抑制剂SU 11274阻断，HGF的这些有益作用就会消失。此外，HGF显著抑制HG刺激的糖原合成酶激酶3 β（GSK 3 β）活性。因此，使用腺病毒载体系统（Ad-GSK 3 β-S9 A）的外源性组成型活性GSK 3 β过表达消除了HGF改善HG介导的足细胞损伤的能力，而野生型GSK 3 β的腺病毒介导的过表达（Ad-GSK 3 β-WT）和失活GSK 3 β突变体的腺病毒转导（Ad-GSK 3 β-K85 A）都不能抵消HGF对HG处理的足细胞的保护作用。总的来说，这些结果表明，HGF通过自噬促进机制（涉及GSK 3 β抑制）预防HG诱导的足细胞损伤。
Podocyte injury or loss plays a major role in the pathogenesis of proteinuric kidney disease including diabetic nephropathy (DN). High basal level of autophagy is critical for podocyte health. Recent studies have revealed that hepatocyte growth factor (HGF) can ameliorate podocyte injury and proteinuria. However, little is known about the impact of HGF on podocyte autophagy. In this study, we investigated whether and how HGF affects autophagy in podocytes treated with high glucose (HG) conditions. HGF significantly diminishes apoptosis, oxidative stress and autophagy impairment inflicted by HG in podocytes. These beneficial effects of HGF disappear once HGF receptor is blocked by SU11274, a specific inhibitor of c-Met. Moreover, HGF markedly suppresses HG-stimulated glycogen synthase kinase 3beta (GSK3β) activity. Accordingly, exogenous constitutively-active GSK3β overexpression using an adenoviral vector system (Ad-GSK3β-S9A) abrogates the ability of HGF to ameliorate HG-mediated podocyte injury while neither adenoviral-mediated overexpression of wild-type GSK3β (Ad-GSK3β-WT) nor adenoviral transduction of inactive GSK3β mutant (Ad-GSK3β-K85A) can counteract the protective effects of HGF on HG-treated podocytes. Collectively, these results suggest that HGF prevents HG-induced podocyte injury via an autophagy-promoting mechanism, which involves GSK3β inhibition.