Quinolinic Acid Excess May Promote Kidney Fibrosis

Background: Acute kidney injury (AKI) and chronic kidney disease (CKD) are characterized by decreased NAD+ biosynthesis. The de novo NAD+ pathway, one of the three pathways for NAD+ biosynthesis, involves quinolinic acid, a metabolite catalyzed by quinolinate phosphoribosyl transferase (QPRT) and converted into NAD+. Primarily recognized as a neurotoxin acting through the NMDA receptor, little is known about quinolinic acid’s kidney effects. We hypothesized that sustained accumulation of quinolinic acid might worsen renal health and favor fibrosis. Methods: We used 8-week-old wild-type C57BL/6 male mice. Two injury models were employed: an acute injury with cisplatin 25 mg/kg harvested on day 3 and a CKD model with folic acid (FA) 250 mg/kg harvested on day 14. We primarily measured fibrosis and kidney injury markers using qPCR, serum BUN, and creatinine. We compared 8 to 72-week-old wild-type (WT) mice. We generated conditional inducible mice that overexpress QPRT with doxycycline 0.2 mg/mL. FA model WT mice were harvested at 0, 36 hours, day 7, and day 14 for metabolomics analysis. Quinolinic acid 0.5 g/L was administered for 14 days, and for 28 days with the FA model starting at day 14. Cell cultures assessed the profibrotic effect of quinolinic acid (1 μM). Memantine 250 nM was applied to pericytes +/- quinolinic acid. Results: Our results verified the age-related decline in QPRT and the progressive accumulation of quinolinic acid with CKD development. Renal tubular induction of the QPRT enzyme reduced excess quinolinic acid and protected renal function in mice induced with cisplatin. Excessive quinolinic acid administration achieved serum levels comparable to CKD and was sufficient to worsen baseline renal function. Introducing quinolinic acid in the FA model exacerbated kidney damage. Application of quinolinic acid to various cell types revealed a specific profibrotic response exclusively in pericytes, a population of cells responsible for fibrosis. Memantine, a NMDA receptor antagonist, protected pericytes from the fibrotic effects of quinolinic acid. Conclusion: Quinolinic acid accumulation may contribute directly to CKD progression. As CKD progresses, the QPRT enzyme expression decreases, and quinolinic acid accumulates. This metabolite may act through NMDA receptors on pericytes to promote a fibrogenic program. Further studies may unveil new ways to target renal fibrosis. Funding: NIDDK Support - NIDDK Support, NIDDK Support