Temporal Profile of Kynurenine Pathway Metabolites in a Rodent Model of Autosomal Recessive Polycystic Kidney Disease
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 d...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2022-10-01
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| Series: | International Journal of Tryptophan Research |
| Online Access: | https://doi.org/10.1177/11786469221126063 |
| _version_ | 1811161901186416640 |
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| author | Ananda Staats Pires Shabarni Gupta Sean A Barton Roshana Vander Wall Vanessa Tan Benjamin Heng Jacqueline K Phillips Gilles J Guillemin |
| author_facet | Ananda Staats Pires Shabarni Gupta Sean A Barton Roshana Vander Wall Vanessa Tan Benjamin Heng Jacqueline K Phillips Gilles J Guillemin |
| author_sort | Ananda Staats Pires |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T06:21:28Z |
| format | Article |
| id | doaj.art-4382a3a482c14488ad53eabc0c7bdaf2 |
| institution | Directory Open Access Journal |
| issn | 1178-6469 |
| language | English |
| last_indexed | 2024-04-10T06:21:28Z |
| publishDate | 2022-10-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | International Journal of Tryptophan Research |
| spelling | doaj.art-4382a3a482c14488ad53eabc0c7bdaf22023-03-02T04:33:09ZengSAGE PublishingInternational Journal of Tryptophan Research1178-64692022-10-011510.1177/11786469221126063Temporal Profile of Kynurenine Pathway Metabolites in a Rodent Model of Autosomal Recessive Polycystic Kidney DiseaseAnanda Staats Pires0Shabarni Gupta1Sean A Barton2Roshana Vander Wall3Vanessa Tan4Benjamin Heng5Jacqueline K Phillips6Gilles J Guillemin7Laboratório de Bioenergética e Estresse Oxidativo, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, BrasilAutonomic and Sensory Neuroscience Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaAutonomic and Sensory Neuroscience Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaAutonomic and Sensory Neuroscience Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaNeuroinflammation Group, Macquarie Medical School, Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaNeuroinflammation Group, Macquarie Medical School, Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaAutonomic and Sensory Neuroscience Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaNeuroinflammation Group, Macquarie Medical School, Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaAutosomal 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.https://doi.org/10.1177/11786469221126063 |
| spellingShingle | Ananda Staats Pires Shabarni Gupta Sean A Barton Roshana Vander Wall Vanessa Tan Benjamin Heng Jacqueline K Phillips Gilles J Guillemin Temporal Profile of Kynurenine Pathway Metabolites in a Rodent Model of Autosomal Recessive Polycystic Kidney Disease International Journal of Tryptophan Research |
| title | Temporal Profile of Kynurenine Pathway Metabolites in a Rodent Model of Autosomal Recessive Polycystic Kidney Disease |
| title_full | Temporal Profile of Kynurenine Pathway Metabolites in a Rodent Model of Autosomal Recessive Polycystic Kidney Disease |
| title_fullStr | Temporal Profile of Kynurenine Pathway Metabolites in a Rodent Model of Autosomal Recessive Polycystic Kidney Disease |
| title_full_unstemmed | Temporal Profile of Kynurenine Pathway Metabolites in a Rodent Model of Autosomal Recessive Polycystic Kidney Disease |
| title_short | Temporal Profile of Kynurenine Pathway Metabolites in a Rodent Model of Autosomal Recessive Polycystic Kidney Disease |
| title_sort | temporal profile of kynurenine pathway metabolites in a rodent model of autosomal recessive polycystic kidney disease |
| url | https://doi.org/10.1177/11786469221126063 |
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