Na+/H+ exchanger-1 reduces podocyte injury caused by endoplasmic reticulum stress via autophagy activation
Na+/H+ exchanger-1 reduces podocyte injury caused by endoplasmic reticulum stress via autophagy activation
复制标题
Na /H 交换器-1 通过自噬激活减轻内质网应激引起的足细胞损伤
DOI：
10.1038/labinvest.2014.4
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发表时间：
2014-04-01
影响因子：
5
通讯作者：
Chen, Xiangmei
中科院分区：
文献类型：
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作者：
Feng, Zhe;Tang, Li;Chen, Xiangmei
足细胞损伤在蛋白尿的发病机制中具有关键作用。内质网（ER）应激的诱导被认为会导致足细胞损伤;然而，没有有效的策略来减少ER应激诱导的损伤已被确定。我们研究了减少ER应激引起的足细胞损伤的具体机制。我们发现，在大鼠被动Heymann肾炎模型中，足细胞中ER应激的诱导与细胞骨架损伤和蛋白尿增加有关，这与自噬激活和Na（+）/H（+）交换器-1（NHE-1）的下调有关。以小鼠足细胞（MPC）为研究对象，我们发现ER应激可导致足细胞损伤并伴有自噬激活，而自噬的紊乱加剧了ER应激条件下细胞骨架的丢失。自噬激活和内质网应激之间的平衡对足细胞存活至关重要，其中自噬的效率可能具有关键作用。引人注目的是，NHE-1的过表达和小干扰RNA敲低结果表明，NHE-1通过减少暴露于ER应激的MPC中突触足蛋白的损失而发挥保护作用。这种保护机制涉及NHE-1通过PI 3 K/Akt途径激活自噬以减少足细胞中的ER应激损伤。这一机制可能为足细胞损伤的防治提供新的途径。
Podocyte injury has a critical role in the pathogenesis of proteinuria. Induction of endoplasmic reticulum (ER) stress is thought to lead to podocyte injury; however, no effective strategy for reducing ER stress-induced injury has been identified. We investigated specific mechanisms for reducing podocyte injury caused by ER stress. We found that the induction of ER stress in podocytes was related to cytoskeleton injury and increased proteinuria, which was associated with autophagy activation and downregulation of Na(+)/H(+) exchanger-1 (NHE-1) in the rat model of passive Heymann nephritis. Using mouse podocyte cells (MPCs), we showed that ER stress could lead to podocyte injury accompanied by autophagy activation, and the disturbance of autophagy aggravated cytoskeleton loss under conditions of ER stress. The balance between autophagy activation and ER stress was critical to podocyte survival, in which the efficiency of autophagy could have a pivotal role. Strikingly, the overexpression and small interfering RNA knockdown of NHE-1 results suggested that NHE-1 exerts a protective effect by reducing the loss of synaptopodin in MPCs exposed to ER stress. This protective mechanism involves NHE-1 activation of autophagy via the PI3K/Akt pathway to reduce ER stress injury in podocytes. This mechanism may provide a new pathway to prevent podocyte injury.