Work

Impaired Metabolic Remodeling Characterizes Injured Niches during Post-ischemic Kidney Repair

Year: 2026

Type: article

Abstract: KEY POINTS: Spatial metabolomics revealed persistent injured tissue niches after ischemic injury despite the presence of apparently healthy epithelial cells. Proximal tubule cells residing in injured niches exhibited succinate accumulation and linoleic acid depletion. Integration with spatial transcriptomics showed that injured niches were characterized by dysregulated oxidative and lipid metabolism. BACKGROUND: The role of the tissue microenvironment in the transition from AKI to CKD remains poorly understood. While the persistence of failed-repair proximal tubule (FR-PT) cells is postulated to hamper kidney regeneration, the spatial metabolic architecture of injured tissue and its effect on regenerative capacity have not been fully characterized. METHODS: We analyzed mouse kidneys 14 days after bilateral ischemia-reperfusion injury using a multimodal spatial omics approach. Internal standard-normalized mass spectrometry imaging was used to quantify metabolite abundances, followed by unsupervised spatial domain analysis using the BANKSY algorithm to identify tissue niches on the basis of lipidome profiles. Consecutive sections underwent high-resolution spatial transcriptomics (Stereo-seq), and we applied niche projection to integrate metabolomic and transcriptomic data, enabling comparison of proximal tubule cells in healthy versus injured niches. RESULTS: Unsupervised spatial domain analysis revealed distinct healthy and injured niches, with injured niches exhibiting diffusely spread metabolic abnormalities extending beyond FR-PT cells. Quantitative metabolomics demonstrated that seemingly healthy proximal tubule cells residing in injured niches exhibited elevated succinic acid and depleted linoleic acid compared with cells in healthy niches. Spatial transcriptomics confirmed these metabolic defects at the transcriptional level, revealing downregulation of oxidative phosphorylation and fatty acid β -oxidation pathways in proximal tubule cells within injured microenvironments. CONCLUSIONS: Combined spatially resolved analysis of internal standard-normalized mass spectrometry imaging and spatial transcriptomics revealed distinct healthy and injured tissue niches after ischemia-reperfusion injury. Metabolic abnormalities, including defects in oxidative phosphorylation and fatty acid β -oxidation, were not restricted to FR-PT cells but extended into seemingly healthy epithelial cells embedded within injured microenvironments.

Source: Journal of the American Society of Nephrology

DOI: 10.1681/asn.0000001216