Temporal Profile of Kynurenine Pathway Metabolites in a Rodent Model of Autosomal Recessive Polycystic Kidney Disease

Abstract

Autosomal recessive polycystic kidney disease (ARPKD) is an early onset genetic disorder characterized by numerous renal cysts resulting in end stage renal disease. Our study aimed to determine if metabolic reprogramming and tryptophan (Trp) metabolism via the kynurenine pathway (KP) is a critical dysregulated pathway in PKD. Using the Lewis polycystic kidney (LPK) rat model of PKD and Lewis controls, we profiled temporal trends for KP metabolites in plasma, urine, and kidney tissues from 6- and 12-week-old mixed sex animals using liquid and gas chromatography, minimum n = 5 per cohort. A greater kynurenine (KYN) concentration was observed in LPK kidney and plasma of 12-week rats compared to age matched Lewis controls ( P ⩽ .05). LPK kidneys also showed an age effect ( P ⩽ .05) with KYN being greater in 12-week versus 6-week LPK. The metabolites xanthurenic acid (XA), 3-hydroxykynurenine (3-HK), and 3-hydroxyanthranilic acid (3-HAA) were significantly greater in the plasma of 12-week LPK rats compared to age matched Lewis controls ( P ⩽ .05). Plasma XA and 3-HK also showed an age effect ( P ⩽ .05) being greater in 12-week versus 6-week LPK. We further describe a decrease in Trp levels in LPK plasma and kidney (strain effect P ⩽ .05). There were no differences in KP metabolites in urine between cohorts. Using the ratio of product and substrates in the KP, a significant age-strain effect ( P ⩽ .05) was observed in the activity of the KYN/Trp ratio (tryptophan-2,3-dioxygenase [TDO] or indoleamine-2,3-dioxygenase [IDO] activity), kynurenine 3-monooxygenase (KMO), KAT A (kynurenine aminotransferase A), KAT B, total KAT, total KYNU (kynureninase), KYNU A, KYNU B, and total KYNU within LPK kidneys, supporting an activated KP. Confirmation of the activation of these enzymes will require verification through orthogonal techniques. In conclusion, we have demonstrated an up-regulation of the KP in alignment with progression of renal impairment in the LPK rat model, suggesting that KP activation may be a critical contributor to the pathobiology of PKD.

Effect of fenofibrate and gemfibrozil on kynurenic acid production in rat kidney in vitro: old drugs, new possibilities

“…Similar observations were made by Klawitter et al, who reported correlation between plasma KYNA level, immune activation and CKD severity in patients with autosomal dominant polycystic kidney disease (Klawitter et al 2022). Interestingly, a recent paper by Pires et al on the Lewis polycystic kidney (LPK) rat model not only demonstrated age dependent KYN accumulation in the plasma and the kidney but also showed stimulation of enzymatic Trp degradation, namely through increased activity of KATs (Pires et al 2022). Since KYN and its metabolites are classi ed as uremic toxins, inhibitory effect of brates on KYNA synthesis should be considered as novel mechanism of kidney protection.…”

Effects of Fenofibrate and Gemfibrozil on Kynurenic Acid Production in Rat Kidneys In Vitro: Old Drugs, New Properties

“…The circulating levels of KYN, KYNA and other kynurenines are related to the severity of diabetic CKD [30,31]. Similarly, the correlation between plasma KYNA levels, immune system activation and CKD severity was described in animal models and in patients with autosomal dominant polycystic kidney disease (ADPKD) [32,33].…”

Alteration in kynurenine pathway metabolites in young women with autoimmune thyroiditis

“…The activity of KP enzymes was calculated indirectly by the determination of product-to-substrate ratios 36 . KYN/TRP ratio, a clinical index of TDO/IDO1 activity (Fig.…”