期刊
CELL REPORTS
卷 29, 期 5, 页码 1261-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2019.09.050
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资金
- Japan Society for the Promotion of Science [16K09604, 18H06192, 16K15464, 18H02824, 15KT0088, 16K15465, 18H02727]
- Kyowa Kirin, Co., Ltd., Japan
- Isotope Science Center, The University of Tokyo
- Grants-in-Aid for Scientific Research [16K15464, 16K09604, 18H06192, 16K15465] Funding Source: KAKEN
Acute kidney injury (AKI) is characterized by mitochondrial dysfunction and activation of the innate immune system. The cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway detects cytosolic DNA and induces innate immunity. Here, we investigate the role of mitochondrial damage and subsequent activation of the cGAS-STING pathway using a genetically engineered animal model of cisplatin-induced AKI and cultured tubular cells. Cisplatin induced mtDNA leakage into the cytosol-probably through BCL-2-like protein 4 (BAX) pores in the mitochondrial outer membrane-in tubules, with subsequent activation of the cGAS-STING pathway, thereby triggering inflammation and AKI progression, which is improved in STING-deficient mice. STING knockdown in cultured tubular cells ameliorates inflammatory responses induced by cisplatin. mtDNA depletion and repletion studies support tubular inflammatory responses via the cGAS-STING signal activation by cytosolic mtDNA. Therefore, we conclude that mitochondrial dysfunction and subsequent activation of the mtDNAc-GAS-STING pathway is a critical regulator of kidney injury.
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