期刊
AUTOPHAGY
卷 17, 期 10, 页码 2975-2990出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2020.1848971
关键词
Acute kidney injury; contrast media; hypoxia inducible factor; mitophagy; NLRP3 inflammasome
类别
资金
- National Natural Science Foundation of China [81770666, 81570604, 81370794, 81700586]
- Shanghai Municipal Health Commission and Family Planning [ZY (2018-2020)-FWTX-1001]
- Shanghai Municipal Commission of Health and Family Planning [ZHYY-ZXYJHZX-1-02]
- Office for Traditional Chinese Medicine Development of Shanghai [ZHYY-ZXYJHZX-1-02]
- Shanghai Sailing Program [20YF1424900]
- Public health Industry Project of Shanghai Municipal Health commission [20194Y0332]
- Outstanding Youth Project from Shanghai key laboratory of nucleic acid chemistry and nanomedicine [2020ZYA002]
This study elucidated a novel mechanism in which NLRP3 inflammasome inhibition attenuated apoptosis and upregulated HIF1A and BNIP3-mediated mitophagy in CI-AKI, indicating the potential applications of MCC950 and roxadustat in clinical CI-AKI treatment.
The pathogenetic mechanism of contrast-induced acute kidney injury (CI-AKI), which is the third most common cause of hospital-acquired AKI, has not been elucidated. Previously, we demonstrated that renal injury and cell apoptosis were attenuated in nlrp3 knockout CI-AKI mice. Here, we investigated the mechanism underlying NLRP3 inhibition-mediated attenuation of apoptosis in CI-AKI. The RNA sequencing analysis of renal cortex revealed that the nlrp3 or casp1 knockout CI-AKI mice exhibited upregulated cellular response to hypoxia, mitochondrial oxidation, and autophagy when compared with the wild-type (WT) CI-AKI mice, which indicated that NLRP3 inflammasome inhibition resulted in the upregulation of hypoxia signaling pathway and mitophagy. The nlrp3 or casp1 knockout CI-AKI mice and iohexol-treated HK-2 cells with MCC950 pretreatment exhibited upregulated levels of HIF1A, BECN1, BNIP3, and LC3B-II, as well as enhanced colocalization of LC3B with BNIP3 and mitochondria, and colocalization of mitochondria with lysosomes. Additionally, roxadustat, a HIF prolyl-hydroxylase inhibitor, protected the renal tubular epithelial cells against iohexol-induced injury through stabilization of HIF1A and activation of downstream BNIP3-mediated mitophagy in vivo and in vitro. Moreover, BNIP3 deficiency markedly decreased mitophagy, and also significantly exacerbated apoptosis and renal injury. This suggested the protective function of BNIP3-mediated mitophagy in CI-AKI. This study elucidated a novel mechanism in which NLRP3 inflammasome inhibition attenuated apoptosis and upregulated HIF1A and BNIP3-mediated mitophagy in CI-AKI. Additionally, this study demonstrated the potential applications of MCC950 and roxadustat in clinical CI-AKI treatment.
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