Activation of BNIP3-mediated mitophagy protects against renal ischemia-reperfusion injury
Activation of BNIP3-mediated mitophagy protects against renal ischemia-reperfusion injury
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激活 BNIP3 介导的线粒体自噬可预防肾缺血再灌注损伤
DOI：
10.1038/s41419-019-1899-0
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发表时间：
2019-09-12
影响因子：
9
通讯作者：
Dong, Zheng
中科院分区：
文献类型：
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作者：
Tang, Chengyuan;Han, Hailong;Dong, Zheng
急性肾损伤（acute kidney injury，阿基）是一种肾功能突然丧失的综合征。阿基的潜在病理机制在很大程度上仍然未知。BCL 2相互作用蛋白3（BNIP 3）具有调节细胞死亡和线粒体自噬的双重功能，但其在阿基中的病理生理作用尚不清楚。在这里，我们证明了BNIP 3表达的增加，在培养的肾近端肾小管上皮细胞后，氧-葡萄糖剥夺-再灌注（OGD-R）和肾小管后，肾缺血-再灌注（IR）诱导的损伤小鼠。在功能上，在培养的肾小管细胞中通过特异性短发夹RNA沉默Bnip 3减少了OGD-R诱导的线粒体自噬，并增强了OGD-R诱导的细胞死亡。在体内，Bnip 3基因敲除加重了肾IR损伤，表现为更严重的肾功能障碍和组织损伤。我们进一步表明，BNIP 3基因敲除减少线粒体自噬，这导致受损线粒体的积累，活性氧的产生增加，并增强细胞死亡和肾脏IR后的炎症反应。总之，这些研究结果表明，BNIP 3介导的线粒体自噬在阿基期间的线粒体质量控制和肾小管细胞存活中具有关键作用。
Acute kidney injury (AKI) is a syndrome of abrupt loss of renal functions. The underlying pathological mechanisms of AKI remain largely unknown. BCL2-interacting protein 3 (BNIP3) has dual functions of regulating cell death and mitophagy, but its pathophysiological role in AKI remains unclear. Here, we demonstrated an increase of BNIP3 expression in cultured renal proximal tubular epithelial cells following oxygen-glucose deprivation-reperfusion (OGD-R) and in renal tubules after renal ischemia–reperfusion (IR)-induced injury in mice. Functionally, silencingBnip3by specific short hairpin RNAs in cultured renal tubular cells reduced OGD-R-induced mitophagy, and potentiated OGD-R-induced cell death. In vivo,Bnip3knockout worsened renal IR injury, as manifested by more severe renal dysfunction and tissue injury. We further showed thatBnip3knockout reduced mitophagy, which resulted in the accumulation of damaged mitochondria, increased production of reactive oxygen species, and enhanced cell death and inflammatory response in kidneys following renal IR. Taken together, these findings suggest that BNIP3-mediated mitophagy has a critical role in mitochondrial quality control and tubular cell survival during AKI.