| First Author | Summers BS | Year | 2025 |
| Journal | PLoS One | Volume | 20 |
| Issue | 12 | Pages | e0335906 |
| PubMed ID | 41343438 | Mgi Jnum | J:376430 |
| Mgi Id | MGI:8269831 | Doi | 10.1371/journal.pone.0335906 |
| Citation | Summers BS, et al. (2025) Renal and hepatic function is preserved following inducible knockout of kynurenine pathway enzymes KMO or QPRT in adult mice. PLoS One 20(12):e0335906 |
| abstractText | The kynurenine pathway (KP) is the canonical route by which tryptophan is metabolised, almost all of which occurs in the liver, with significant expression of its enzymes also known in the kidney. We generated two novel mouse models for inducible global knockout of midpoint KP enzyme kynurenine-3-monooxygenase (KMO) and endpoint enzyme quinolinate phosphoribosyltransferase (QPRT; converts known neurotoxic KP metabolite Quinolinic acid to nicotinamide adenine dinucleotide (NAD) precursor via the de novo synthesis pathway). The KP is dysregulated in many renal and hepatic disorders, but as an essential step prior to use in disease studies, we set out to characterise their basal KP metabolome and investigate any changes to their overall phenotype in the liver and kidney, free of exogenous inflammatory stimuli. Both enzyme knockouts caused rapid alterations in accumulation of blood metabolite levels upstream of the affected enzyme, although downstream metabolite concentrations were surprisingly unaffected. KMO knockout elevated kynurenine, kynurenic acid and anthranilic acid, while QPRT knockout elevated quinolinic acid. Regardless of these significant metabolic alterations, histological examination of liver and kidney tissues, standard clinical blood chemistry and gross animal observations indicated no evidence of pathological changes in both the renal and hepatic systems. Our findings suggest that in a timeframe of 1-5 weeks and without evoked inflammation, robust homeostatic mechanisms can accommodate substantial fluctuations in KP metabolite concentrations in knockout mice without affecting renal or hepatic structure or function. |
