Spatial metabolomics reveals persistent localized niche-specific metabolic failure in kidneys following ischemia-reperfusion injury

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

ABSTRACT After acute kidney injury (AKI), the persistence of failed repair proximal tubule (FR-PT) cells is postulated to hamper kidney regeneration and increase the risk of chronic kidney disease. This fibrotic shift likely depends on microenvironmental interactions, which remain largely unstudied. To investigate this, we mapped the spatial metabolic architecture of post-ischemic kidneys using an untargeted semi-quantitative spatial metabolomics (qMSI) approach, integrated with high-resolution spatial transcriptomics. Unsupervised neighborhood clustering of qMSI data revealed distinct microenvironments. Lipidome profiles identified diffusely spread areas with persistent injury markers surrounding FR-PT cells. These niches exhibited decreased linoleic acid and elevated succinic acid levels, even in epithelial cells that appeared otherwise healthy. Corresponding transcriptomic profiles confirmed downregulation of oxidative phosphorylation and fatty acid β-oxidation in these regions. Together, these findings point towards niche-specific metabolic failure and persistent mitochondrial dysfunction in areas considered healthy, underscoring the need to prioritize metabolic resuscitation to prevent long-term consequences of AKI.

Authors 8

1. Rosalie G. J. Rietjens Aachen Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands

2. Benedetta Manzato Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

3. Bernard M. van den Berg Aachen Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands

4. Ahmed Essam Mahfouz Aachen Department of Human Genetics

   Leiden University Medical Center · Delft University of Technology

   Affiliation as printed

   Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

5. Martin A. Giera Aachen Center for Proteomics and Metabolomics

   Leiden University Medical Center

   Affiliation as printed

   Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands

6. Sébastien J. Dumas Aachen Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine

   Leiden University · Inserm · Leiden University Medical Center · Institut des Maladies Métaboliques et Cardiovasculaires · Université de Toulouse

   Affiliation as printed

   Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands

   National Institute of Health and Medical Research (INSERM), UMR 1297, Institute of Metabolic and Cardiovascular Diseases, University of Toulouse, Toulouse, France

7. Gangqi Wang corresponding Aachen Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine

   Leiden University · Fudan University · Leiden University Medical Center · Children's Hospital of Fudan University

   Affiliation as printed

   Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China

   Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands

8. Ton J. Rabelink corresponding Aachen Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands