期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 554, 期 -, 页码 158-165出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2021.03.103
关键词
Ascorbate; Mitophagy; Septic AKI; PINK1-PARK2 axis
资金
- Natural Science Foundation of Zhejiang Province [LY19H020001, LQ20H150009]
- National Natural Science Foundation of China [81971857]
- Zhejiang Key R&D Project of Science Technology Department of Zhejiang Province [2019C03024]
This study revealed that activation of Toll-like receptor 4 (TLR4) by LPS stimuli can enhance the uptake of ascorbate in renal tubular cells, providing protection against LPS-induced apoptosis. Additionally, ascorbate administration promotes mitophagy, aiding in the fight against septic acute kidney injury.
Ascorbate (Vitamin C) has been proposed as a promising therapeutic agent against sepsis in clinical trials, but there is little experimental evidence on its anti-septic efficacy. We report that Toll-like receptor 4 (TLR4) activation by LPS stimuli augments ascorbate uptake in murine and human tubular cells through upregulation of two ascorbate transporters SVCT-1 and -2 mediated by Fn14/SCFFbxw7 alpha cascade. Ascorbate restriction, or knockout of SVCT-1 and -2, the circumstance reminiscent to blockade of ascorbate uptake, endows tubular cells more vulnerable to the LPS-inducible apoptosis, whereas exogenous administration of ascorbate overrides the ruin execution, for which the PINK1-PARK2, rather than BNIP3-NIX axis is required. Ascorbate increases, while SVCT-1 and -2 knockout or ascorbate restriction dampens tubular mitophagy upon LPS stimuli. Treatment of endotoxemic mice with high-dose ascorbate confers mitophagy and substantial protection against mortality and septic acute kidney injury (AKI). Our work provides a rationale for clinical management of septic AKI with high doses of ascorbate. (C) 2021 Elsevier Inc. All rights reserved.
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