Quinolinic acid potentially links kidney injury to brain toxicity
Kidney dysfunction often leads to neurological impairment, yet the complex kidney-brain relationship remains elusive. We employed spatial and bulk metabolomics to investigate a mouse model of rapid kidney failure induced by mouse double minute 2 (Mdm2) conditional deletion in the kidney tubules to interrogate kidney and brain metabolism. Pathway enrichment analysis of a focused plasma metabolomics panel pinpointed tryptophan metabolism as the most altered pathway with kidney failure. Spatial metabolomics showed toxic tryptophan metabolites in the kidneys and brains, revealing a connection between advanced kidney disease and accelerated kynurenine degradation. In particular, the excitotoxic metabolite quinolinic acid was localized in ependymal cells in the setting of kidney failure. These findings were associated with brain inflammation and cell death. Separate mouse models of ischemia-induced acute kidney injury and adenine-induced chronic kidney disease also exhibited systemic inflammation and accumulating toxic tryptophan metabolites. Patients with advanced chronic kidney disease (stage 3b-4 and stage 5) similarly demonstrated elevated plasma kynurenine metabolites, and quinolinic acid was uniquely correlated with fatigue and reduced quality of life. Overall, our study identifies the kynurenine pathway as a bridge between kidney decline, systemic inflammation, and brain toxicity, offering potential avenues for diagnosis and treatment of neurological issues in kidney disease.
Authors
- Meyer Maddox
- Soumya Maity (ORCID: https://orcid.org/0000-0002-3407-1734)
- Falguni Das
- Kevin F. Bieniek (ORCID: https://orcid.org/0000-0003-4922-864X)
- Richard Montellano
- Nagarjunachary Ragi (ORCID: https://orcid.org/0000-0002-2009-525X)
- James D. Lechleiter (ORCID: https://orcid.org/0000-0001-9000-0722)
- Sarah C. Hopp (ORCID: https://orcid.org/0000-0001-5228-0022)
- Jason C. O’Connor (ORCID: https://orcid.org/0000-0002-5901-5640)
- Jana Tůmová (ORCID: https://orcid.org/0000-0003-1625-4737)
- Caitlyn Fastenau (ORCID: https://orcid.org/0000-0002-4729-2712)
- Bernard Fongang (ORCID: https://orcid.org/0000-0002-8161-1553)
- Subrata Debnath (ORCID: https://orcid.org/0000-0003-4245-8450)
- Leila Hejazi
- Guanshi Zhang (ORCID: https://orcid.org/0000-0001-6557-4521)
- Kumar Sharma (ORCID: https://orcid.org/0000-0002-7550-8525)
- Hak Joo Lee (ORCID: https://orcid.org/0000-0003-3954-3216)
- Pragya Singh (ORCID: https://orcid.org/0000-0002-3643-7664)
- Ian M. Tamayo (ORCID: https://orcid.org/0009-0009-1521-2915)
- Afaf Saliba (ORCID: https://orcid.org/0000-0003-2576-4069)
- E.F. Martinez Trevino
- Manjeri A. Venkatachalam
Institutions
- The University of Texas at San Antonio Health Science Center (US)
- Charles University (CZ)
- Institute for Neurodegenerative Disorders (US)
- Precision for Medicine (United States) (US)
Publication Details
- Journal
- JCI Insight
- Published
- 2025-02-13
- DOI
- https://doi.org/10.1172/jci.insight.180229
- Citations
- 10
- Primary Topic
- Metabolism and Genetic Disorders
- Type
- article
- Field-Weighted Citation Impact
- 11.87
Funders
- U.S. Department of Defense
- National Institutes of Health
- University of Texas Health Science Center at San Antonio
- National Heart, Lung, and Blood Institute
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Neurological Disorders and Stroke
- National Center for Advancing Translational Sciences