Genetic Inhibition of Quinolinic Acid Synthesis Reveals Kidney-Brain Inflammatory Cross-Talk in AKI

Background: The kidney-brain axis plays a critical role in mediating systemic consequences of acute kidney injury (AKI), yet its molecular drivers remain poorly characterized. Recent work demonstrated that quinolinic acid (QA), a neurotoxic tryptophan metabolite, accumulates in the kidney, plasma, and brain during kidney injury. However, the mechanistic and therapeutic implications of QA remain to be elucidated. Methods: We utilized cisplatin-induced AKI model in male C57BL/6N mice (n=4-5/group). Mice were injected intraperitoneally with saline or cisplatin (20 mg/kg) and sacrificed 72 hours post-injection. Two germline knockout lines were used: Haao-/- and Kmo-/- mice, which lack the enzymes 3-hydroxyanthranilate 3,4-dioxygenase (HAAO) and kynurenine 3-monooxygenase (KMO), both of which catalyze key kynurenine pathway steps leading to QA synthesis. Kidney injury was assessed. QA levels were measured using LC-MS. Neuroinflammatory gene expression was quantified in brain tissue. To assess clinical relevance, plasma QA levels were analyzed in hemodialysis patients (n=29) before and after a single dialysis session. Results: Both Haao-/- and Kmo-/- mice were significantly protected from cisplatin-induced AKI, with lower BUN (p<0.001), plasma creatinine (p<0.001), Kim1 (p<0.05), Lcn2 (p<0.05), and Nfil3 (p<0.05) expression compared to cisplatin-treated WT mice. QA levels were nearly undetectable in Haao-/- and Kmo-/- mice across plasma, kidney and brain (p<0.001), confirming metabolic blockade. Brain inflammation markers (Ccl2, Tnf, Nfil3) were also significantly reduced in Haao-/- and Kmo-/- mice (p<0.05). In human plasma, QA was dialyzable with a mean reduction of 94.8% post-hemodialysis (p<0.001), confirming QA’s systemic circulation and clearance potential. Conclusion: Our data define QA as mechanistic effector of kidney-brain crosstalk and driver of neuroinflammation following kidney injury. Genetic ablation of Haao and Kmo confers marked kidney protection and suppresses brain inflammatory signaling, positioning the kynurenine pathway as a dual-organ therapeutic target. The dialyzability of QA in humans reinforces its translational relevance and supports targeting this metabolite in future therapeutic strategies to mitigate renal and neurologic sequelae of kidney disease. Funding: NIDDK Support - NIDDK Support, NIDDK Support, Veterans Affairs Support