Spatially resolved multi-omics unravels region-specific responses, microenvironment remodeling and metabolic reprogramming in aristolochic acid nephropathy
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GRAPHICAL ABSTRACT
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PUBLIC SUMMARY
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Aristolochic acid I (AAI)-induced renal injury exhibits heterogeneity of response along nephron segment.
AAI extensively remodels cellular crosstalk between proximal tubule (PT) cells and immune cells.
AAI induces metabolic reprogramming in PT cells, especially the up-regulation of purine metabolism.
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ABSTRACT
Aristolochic acid nephropathy (AAN), primarily caused by overexposure to aristolochic acid I (AAI), is characterized by acute renal injury, interstitial nephritis, and metabolic dysfunction. Previous studies have revealed the cell-specific responses to AAI and its role in inducing metabolic dysfunction. However, the lack of structural information in these datasets hinders our full understanding of the spatially specific pathological mechanisms of AAN. To address this limitation, we propose an integration of spatial transcriptomics with spatial metabolomics methods to establish a spatial multi-omics analysis, which allows for deciphering region-specific responses, microenvironmental remodeling, and metabolic reprogramming in situ in AAN. The pathological differences between renal regions indicate that AAI-induced renal injury exhibits spatial heterogeneity. With prolonged AAI treatment, we observed an increased proportion and co-localization of the injured proximal tubule (PT-inj) and immune cells in the cortex region, accompanied by intercellular crosstalk involving the MHC-I and CCL pathways. In addition, we identified a divergent cellular response along nephron segments, with up-regulation of multiple renal stress markers and pathways after AAI treatment. Regional heterogeneity of metabolic activities was also observed, with PT-inj cells exhibiting dysregulation of carbohydrate, lipid, and amino acid metabolic pathways, as well as increased purine and pyrimidine metabolism after AAI treatment. These findings provide a more comprehensive understanding of the cellular and molecular mechanisms of AAN in a spatial context, and suggest potential intervention pathways to alleviate the global burden of AAN. -
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REFERENCES
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Chen J., Li H., Bai Y., et al., (2024). Spatially resolved multi-omics unravels region-specific responses, microenvironment remodeling and metabolic reprogramming in aristolochic acid nephropathy. The Innovation Medicine 2(2): 100066. https://doi.org/10.59717/j.xinn-med.2024.100066
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Chen J., Li H., Bai Y., et al., (2024). Spatially resolved multi-omics unravels region-specific responses, microenvironment remodeling and metabolic reprogramming in aristolochic acid nephropathy. The Innovation Medicine 2(2): 100066. https://doi.org/10.59717/j.xinn-med.2024.100066
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Figure 1.
Establishment of an AAN mouse model for spatially resolved multi-omics analysis
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Figure 2.
Spatial transcriptomics of kidney samples from the healthy and AAN mice
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Figure 3.
Analysis of the spatial cellular interactions in AAI-treated mouse kidney
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Figure 4.
Regional response to AAI-induced kidney injury
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Figure 5.
Metabolic reprogramming of different spot types in the AAN
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Figure 6.
Spatial metabolomic landscape of the AAN mouse kidney sample
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Figure 7.
Differentially expressed metabolites and pathway enrichment at the CTX region
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Figure 8.
Activation of the purine metabolic pathway of injured PT cells in the AAN
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