TY - JOUR
T1 - Quinolinic acid potentially links kidney injury to brain toxicity
AU - Saliba, Afaf
AU - Debnath, Subrata
AU - Tamayo, Ian
AU - Lee, Hak Joo
AU - Ragi, Nagarjunachary
AU - Das, Falguni
AU - Montellano, Richard
AU - Tumova, Jana
AU - Maddox, Meyer
AU - Trevino, Esmeralda
AU - Singh, Pragya
AU - Fastenau, Caitlyn
AU - Maity, Soumya
AU - Zhang, Guanshi
AU - Hejazi, Leila
AU - Venkatachalam, Manjeri A.
AU - O’Connor, Jason C.
AU - Fongang, Bernard
AU - Hopp, Sarah C.
AU - Bieniek, Kevin F.
AU - Lechleiter, James D.
AU - Sharma, Kumar
N1 - Publisher Copyright:
© 2025, Saliba et al.
PY - 2025/3/24
Y1 - 2025/3/24
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.180229
DO - 10.1172/jci.insight.180229
M3 - Article
C2 - 39946208
AN - SCOPUS:105001197504
SN - 2379-3708
VL - 10
JO - JCI Insight
JF - JCI Insight
IS - 6
M1 - e180229
ER -