| RRC ID |
87346
|
| 著者 |
Ni Y, Wu GH, Cai JJ, Zhang R, Zheng Y, Liu JQ, Yang XH, Yang X, Shen Y, Lai JM, Ye XM, Mo SJ.
|
| タイトル |
Tubule-mitophagic secretion of SerpinG1 reprograms macrophages to instruct anti-septic acute kidney injury efficacy of high-dose ascorbate mediated by NRF2 transactivation.
|
| ジャーナル |
Int J Biol Sci
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| Abstract |
High-dose ascorbate confers tubular mitophagy responsible for septic acute kidney injury (AKI) amelioration, yet its biological roles in immune regulation remain poorly understood. Methods: The role of tubular mitophagy in macrophage polarization upon high-dose ascorbate treatment was assessed by fluorescence-activated cell sorter analysis (FACS) in vitro and by immunofluorescence in AKI models of LPS-induced endotoxemia (LIE) from Pax8-cre; Atg7flox/flox mice. The underlying mechanisms were revealed by RNA-sequencing, gene set enrichment analysis (GSEA), luciferase reporter, chromatin immunoprecipitation (ChIP) and adeno-associated viral vector serotype 9 (AAV9) delivery assays. Results: High-dose ascorbate enables conversion of macrophages from a pro-inflammatory M1 subtype to an anti-inflammatory M2 subtype in murine AKI models of LIE, leading to decreased renal IL-1β and IL-18 production, reduced mortality and alleviated tubulotoxicity. Blockade of tubular mitophagy abrogates anti-inflammatory macrophages polarization under the high-dose ascorbate-exposed coculture systems. Similar abrogations are verified in LIE mice with tubular epithelium-specific ablation of Atg7, where the high-dose ascorbate-inducible renal protection and survival improvement are substantially weaker than their control littermates. Mechanistically, high-dose ascorbate stimulates tubular secretion of serpin family G member 1 (SerpinG1) through maintenance of mitophagy, for which nuclear factor-erythroid 2 related factor 2 (NRF2) transactivation is required. SerpinG1 perpetuates anti-inflammatory macrophages to prevent septic AKI, while kidney-specific disruption of SerpinG1 by adeno-associated viral vector serotype 9 (AAV9)-short hairpin RNA (shRNA) delivery thwarts the anti-inflammatory macrophages polarization and anti-septic AKI efficacy of high-dose ascorbate. Conclusion: Our study identifies SerpinG1 as an intermediate of tubular mitophagy-orchestrated myeloid function during septic AKI and reveals a novel rationale for ascorbate-based therapy.
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| 巻・号 |
18(13)
|
| ページ |
5168-5184
|
| 公開日 |
2022-1-1
|
| DOI |
10.7150/ijbs.74430
|
| PII |
ijbsv18p5168
|
| PMID |
35982894
|
| PMC |
PMC9379417
|
| MeSH |
Acute Kidney Injury* / drug therapy
Animals
Ascorbic Acid* / pharmacology
Complement C1 Inhibitor Protein* / genetics
Kidney
Kidney Tubules / metabolism
Macrophages* / drug effects
Mice
Mice, Inbred C57BL
NF-E2-Related Factor 2* / genetics
Transcriptional Activation
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| リソース情報 |
| 実験動物マウス |
RBRC02759 |
