Abstract
Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by some herbal medicines, but treatment remains ineffective. We previously found that leucine-rich α-2-glycoprotein 1 (LRG1), which regulates cellular processes, plays an important role in a kidney injury model. However, the underlying mechanism by which LRG1 regulates AAN is still unknown. In this study, we established an AAN model in vivo, a coculture system of macrophages and TECs, and a macrophage/TEC conditioned media culture model in vitro. We found that macrophage infiltration promoted injury, oxidative stress, and apoptosis in TECs. Furthermore, the role of macrophages in AAN was dependent on macrophage-derived extracellular vesicles (EVs). Importantly, we found that macrophage-derived, LRG1-enriched EVs induced TEC injury and apoptosis via a TGFβR1-dependent process. This study may help design a better therapeutic strategy to treat AAN patients.
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Abbreviations
- AA:
-
Aristolochic acid
- AAN:
-
Aristolochic acid nephropathy
- EV:
-
Extracellular vesicles
- TEC:
-
Tubular epithelial cells
- Cr:
-
Creatinine
- BUN:
-
Blood urea nitrogen
- NOX4:
-
NADPH oxidase 4
- CM:
-
Conditioned medium
- LRG1:
-
Leucine-rich α-2-glycoprotein 1
- HK-2:
-
Human kidney tubular epithelial cells
- mTEC:
-
Mouse kidney tubular epithelial cells
- NTA:
-
Nanoparticle tracking analysis
- TSG101:
-
Tumor susceptibility gene 101
- ARF6:
-
Adenosine diphosphateribosylation factor 6
- PAS:
-
Periodic acid-Schiff
- GME:
-
Glomerular mesangial expansion
- IL:
-
Interleukin
- CXCL:
-
Chemokine (C-X-C motif) ligand
- Cyto D:
-
Cytochalasin D
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Acknowledgements
This work was supported by funding from National Science Foundation of China (U19A2001), Natural Science Foundation of Anhui Province (2008085MH273) and the University Synergy Innovation Programs of Anhui Province (GXXT-2019-045, GXXT-2020-063, GXXT-2020-025). The authors thank the Center for Scientific Research of Anhui Medical University for valuable help in our experiment.
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Jiang, W., Xu, C., Xu, S. et al. Macrophage-derived, LRG1-enriched extracellular vesicles exacerbate aristolochic acid nephropathy in a TGFβR1-dependent manner. Cell Biol Toxicol 38, 629–648 (2022). https://doi.org/10.1007/s10565-021-09666-1
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DOI: https://doi.org/10.1007/s10565-021-09666-1