Spatially resolved multi-omics unravels region-specific responses, microenvironment remodeling and metabolic reprogramming in aristolochic acid nephropathy

Abstract

<p>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 <i>in situ</i> 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.</p>