Autophagy in acute kidney injury.
Autophagy in acute kidney injury.
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DOI：
10.1016/j.kint.2015.11.021
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发表时间：
2016-04
影响因子：
19.6
通讯作者：
Shah SV
中科院分区：
文献类型：
--
作者：
Kaushal GP;Shah SV
自噬是一个保守的多步骤途径，降解和修复受损的细胞器和大分子，以维持细胞内的稳态。自噬途径在应激条件下上调，包括细胞饥饿、缺氧、营养和生长因子剥夺、ER应激和氧化损伤，其中大部分参与急性肾损伤（阿基）的发病机制。最近的研究表明，在肾脏中的基础自噬是至关重要的近端小管的正常稳态。关键自噬蛋白的缺失损害肾功能，增加p62水平和氧化应激。在阿基模型中，近端小管中的自噬缺失使肾小管损伤和肾功能恶化，这凸显了自噬在阿基模型中具有肾保护作用。除了非选择性螯合自噬货物，自噬可以通过线粒体自噬过程促进受损细胞器的选择性降解，特别是线粒体降解。受损的线粒体在缺血再灌注损伤小鼠的自噬缺陷肾脏中积累，但阿基中线粒体自噬调节的精确机制尚未阐明。在鉴定自噬、凋亡和调节性坏死的相互作用方面的最新进展重新引起了人们对检查阿基发病过程中这种串扰中的共享途径/分子的兴趣。自噬及其相关途径为阿基的治疗干预提供了潜在的独特靶点。
Autophagy is a conserved multistep pathway that degrades and recycles damaged organelles and macromolecules to maintain intracellular homeostasis. The autophagy pathway is upregulated under stress conditions including cell starvation, hypoxia, nutrient and growth-factor deprivation, ER stress, and oxidant injury, most of which are involved in the pathogenesis of acute kidney injury (AKI). Recent studies demonstrate that basal autophagy in the kidney is vital for the normal homeostasis of the proximal tubules. Deletion of key autophagy proteins impaired renal function and increased p62 levels and oxidative stress. In models of AKI, autophagy deletion in proximal tubules worsened tubular injury and renal function, highlighting that autophagy is renoprotective in models of AKI. In addition to nonselective sequestration of autophagic cargo, autophagy can facilitate selective degradation of damaged organelles particularly mitochondrial degradation through the process of mitophagy. Damaged mitochondria accumulate in autophagy-deficient kidneys of mice subjected to ischemia-reperfusion injury, but the precise mechanisms of regulation of mitophagy in AKI are not yet elucidated. Recent progress in identifying the interplay of autophagy, apoptosis, and regulated necrosis has revived interest in examining shared pathways/molecules in this crosstalk during the pathogenesis of AKI. Autophagy and its associated pathways pose potentially unique targets for therapeutic interventions in AKI.