Fig. 9

The de novo pathway in CKD. (1) Elevated indoleamine 2,3-dioxygenase 1 (IDO1) activity in CKD increases the transformation of tryptophan into kynurenine. Kynurenine aminotransferases (KAT) and kynurenine 3-monoxygenase (KMO) transform kynurenine into kynurenic acid and 3-hydroxy-l-kynurenine, respectively. (2) Both kynurenine and kynurenic acid bind and activate the aryl hydrocarbon receptor (AHR). AHR transcribes genes with its dimer partner, hypoxia inducible factor (HIF)-1β. AHR ligands are associated with endothelial dysfunction and thrombosis. Kynurenic acid also binds and activates hydroxy-carboxylic acid receptor (HCAR)-3. The binding affinity of these ligands for AHR or HCAR3 and their downstream responses have not been fully explored in CKD. (3) Quinolinic acid (also known as quinolinate) is upregulated in CKD. Higher quinolinic acid levels can be correlated with endothelial dysfunction. Quinolinic acid is also a neurotoxin. Quinolinic acid functions in CKD have not been fully explored. (4) Downregulation of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1 α, which transcribes quinolinate phosphoribosyl transferase (QPRT), prevents the conversion of quinolinic acid into nicotinic acid mononucleotide (NAMN). (5) NAD levels are reduced in CKD. NAD-induced activation of SIRT1 antagonizes the activity of AHR and its downstream responses. Enzymes and molecules altered in CKD are highlighted (see text for additional details)