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Fibroblastic reticular cell-derived exosomes are a promising therapeutic approach for septic acute kidney injury.

Authors :
Li Y
Hu C
Zhai P
Zhang J
Jiang J
Suo J
Hu B
Wang J
Weng X
Zhou X
Billiar TR
Kellum JA
Deng M
Peng Z
Source :
Kidney international [Kidney Int] 2024 Mar; Vol. 105 (3), pp. 508-523. Date of Electronic Publication: 2023 Dec 30.
Publication Year :
2024

Abstract

Sepsis-induced acute kidney injury (S-AKI) is highly lethal, and effective drugs for treatment are scarce. Previously, we reported the robust therapeutic efficacy of fibroblastic reticular cells (FRCs) in sepsis. Here, we demonstrate the ability of FRC-derived exosomes (FRC-Exos) to improve C57BL/6 mouse kidney function following cecal ligation and puncture-induced sepsis. In vivo imaging confirmed that FRC-Exos homed to injured kidneys. RNA-Seq analysis of FRC-Exo-treated primary kidney tubular cells (PKTCs) revealed that FRC-Exos influenced PKTC fate in the presence of lipopolysaccharide (LPS). FRC-Exos promoted kinase PINK1-dependent mitophagy and inhibited NLRP3 inflammasome activation in LPS-stimulated PKTCs. To dissect the mechanism underlying the protective role of Exos in S-AKI, we examined the proteins within Exos by mass spectrometry and found that CD5L was the most upregulated protein in FRC-Exos compared to macrophage-derived Exos. Recombinant CD5L treatment in vitro attenuated kidney cell swelling and surface bubble formation after LPS stimulation. FRCs were infected with a CD5L lentivirus to increase CD5L levels in FRC-Exos, which were then modified in vitro with the kidney tubular cell targeting peptide LTH, a peptide that binds to the biomarker protein kidney injury molecule-1 expressed on injured tubule cells, to enhance binding specificity. Compared with an equivalent dose of recombinant CD5L, the modified CD5L-enriched FRC-Exos selectively bound PKTCs, promoted kinase PINK-ubiquitin ligase Parkin-mediated mitophagy, inhibiting pyroptosis and improved kidney function by hindering NLRP3 inflammasome activation, thereby improving the sepsis survival rate. Thus, strategies to modify FRC-Exos could be a new avenue in developing therapeutics against kidney injury.<br /> (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1523-1755
Volume :
105
Issue :
3
Database :
MEDLINE
Journal :
Kidney international
Publication Type :
Academic Journal
Accession number :
38163633
Full Text :
https://doi.org/10.1016/j.kint.2023.12.007