Metabolomics and Gene Expression Analysis Reveal Down-regulation of the Citric Acid (TCA) Cycle in Non-diabetic CKD Patients
Chronic kidney disease (CKD) is a public health problem with very high prevalence and mortality. Yet, there is a paucity of effective treatment options, partly due to insufficient knowledge of underlying pathophysiology. We combined metabolomics (GCMS) with kidney gene expression studies to identify...
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Elsevier
2017-12-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396417304267 |
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| author | Stein Hallan Maryam Afkarian Leila R. Zelnick Bryan Kestenbaum Shoba Sharma Rintaro Saito Manjula Darshi Gregory Barding Daniel Raftery Wenjun Ju Matthias Kretzler Kumar Sharma Ian H. de Boer |
| author_facet | Stein Hallan Maryam Afkarian Leila R. Zelnick Bryan Kestenbaum Shoba Sharma Rintaro Saito Manjula Darshi Gregory Barding Daniel Raftery Wenjun Ju Matthias Kretzler Kumar Sharma Ian H. de Boer |
| author_sort | Stein Hallan |
| collection | DOAJ |
| description | Chronic kidney disease (CKD) is a public health problem with very high prevalence and mortality. Yet, there is a paucity of effective treatment options, partly due to insufficient knowledge of underlying pathophysiology. We combined metabolomics (GCMS) with kidney gene expression studies to identify metabolic pathways that are altered in adults with non-diabetic stage 3–4 CKD versus healthy adults. Urinary excretion rate of 27 metabolites and plasma concentration of 33 metabolites differed significantly in CKD patients versus controls (estimate range − 68% to +113%). Pathway analysis revealed that the citric acid cycle was the most significantly affected, with urinary excretion of citrate, cis-aconitate, isocitrate, 2-oxoglutarate and succinate reduced by 40–68%. Reduction of the citric acid cycle metabolites in urine was replicated in an independent cohort. Expression of genes regulating aconitate, isocitrate, 2-oxoglutarate and succinate were significantly reduced in kidney biopsies. We observed increased urine citrate excretion (+74%, p = 0.00009) and plasma 2-oxoglutarate concentrations (+12%, p = 0.002) in CKD patients during treatment with a vitamin-D receptor agonist in a randomized trial. In conclusion, urinary excretion of citric acid cycle metabolites and renal expression of genes regulating these metabolites were reduced in non-diabetic CKD. This supports the emerging view of CKD as a state of mitochondrial dysfunction. |
| first_indexed | 2024-12-10T06:02:02Z |
| format | Article |
| id | doaj.art-a4d0f131e2714adf87397a4be51fc2bb |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-10T06:02:02Z |
| publishDate | 2017-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-a4d0f131e2714adf87397a4be51fc2bb2022-12-22T01:59:48ZengElsevierEBioMedicine2352-39642017-12-0126C687710.1016/j.ebiom.2017.10.027Metabolomics and Gene Expression Analysis Reveal Down-regulation of the Citric Acid (TCA) Cycle in Non-diabetic CKD PatientsStein Hallan0Maryam Afkarian1Leila R. Zelnick2Bryan Kestenbaum3Shoba Sharma4Rintaro Saito5Manjula Darshi6Gregory Barding7Daniel Raftery8Wenjun Ju9Matthias Kretzler10Kumar Sharma11Ian H. de Boer12Center for Renal Translational Medicine/Institute for Metabolomic Medicine, University of California San Diego, San Diego, CA, United StatesKidney Research Institute, University of Washington, Seattle, WA, United StatesKidney Research Institute, University of Washington, Seattle, WA, United StatesKidney Research Institute, University of Washington, Seattle, WA, United StatesUniversity of Texas Health San Antonio, San Antonio, TX, United StatesCenter for Renal Translational Medicine/Institute for Metabolomic Medicine, University of California San Diego, San Diego, CA, United StatesCenter for Renal Translational Medicine/Institute for Metabolomic Medicine, University of California San Diego, San Diego, CA, United StatesNorthwest Metabolomics Research Center, University of Washington, Seattle, WA, United StatesNorthwest Metabolomics Research Center, University of Washington, Seattle, WA, United StatesDivision of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, MI, United StatesDivision of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, MI, United StatesCenter for Renal Translational Medicine/Institute for Metabolomic Medicine, University of California San Diego, San Diego, CA, United StatesKidney Research Institute, University of Washington, Seattle, WA, United StatesChronic kidney disease (CKD) is a public health problem with very high prevalence and mortality. Yet, there is a paucity of effective treatment options, partly due to insufficient knowledge of underlying pathophysiology. We combined metabolomics (GCMS) with kidney gene expression studies to identify metabolic pathways that are altered in adults with non-diabetic stage 3–4 CKD versus healthy adults. Urinary excretion rate of 27 metabolites and plasma concentration of 33 metabolites differed significantly in CKD patients versus controls (estimate range − 68% to +113%). Pathway analysis revealed that the citric acid cycle was the most significantly affected, with urinary excretion of citrate, cis-aconitate, isocitrate, 2-oxoglutarate and succinate reduced by 40–68%. Reduction of the citric acid cycle metabolites in urine was replicated in an independent cohort. Expression of genes regulating aconitate, isocitrate, 2-oxoglutarate and succinate were significantly reduced in kidney biopsies. We observed increased urine citrate excretion (+74%, p = 0.00009) and plasma 2-oxoglutarate concentrations (+12%, p = 0.002) in CKD patients during treatment with a vitamin-D receptor agonist in a randomized trial. In conclusion, urinary excretion of citric acid cycle metabolites and renal expression of genes regulating these metabolites were reduced in non-diabetic CKD. This supports the emerging view of CKD as a state of mitochondrial dysfunction.http://www.sciencedirect.com/science/article/pii/S2352396417304267Citric acid cycleChronic kidney diseaseMetabolomicsGene expressionMitochondria |
| spellingShingle | Stein Hallan Maryam Afkarian Leila R. Zelnick Bryan Kestenbaum Shoba Sharma Rintaro Saito Manjula Darshi Gregory Barding Daniel Raftery Wenjun Ju Matthias Kretzler Kumar Sharma Ian H. de Boer Metabolomics and Gene Expression Analysis Reveal Down-regulation of the Citric Acid (TCA) Cycle in Non-diabetic CKD Patients EBioMedicine Citric acid cycle Chronic kidney disease Metabolomics Gene expression Mitochondria |
| title | Metabolomics and Gene Expression Analysis Reveal Down-regulation of the Citric Acid (TCA) Cycle in Non-diabetic CKD Patients |
| title_full | Metabolomics and Gene Expression Analysis Reveal Down-regulation of the Citric Acid (TCA) Cycle in Non-diabetic CKD Patients |
| title_fullStr | Metabolomics and Gene Expression Analysis Reveal Down-regulation of the Citric Acid (TCA) Cycle in Non-diabetic CKD Patients |
| title_full_unstemmed | Metabolomics and Gene Expression Analysis Reveal Down-regulation of the Citric Acid (TCA) Cycle in Non-diabetic CKD Patients |
| title_short | Metabolomics and Gene Expression Analysis Reveal Down-regulation of the Citric Acid (TCA) Cycle in Non-diabetic CKD Patients |
| title_sort | metabolomics and gene expression analysis reveal down regulation of the citric acid tca cycle in non diabetic ckd patients |
| topic | Citric acid cycle Chronic kidney disease Metabolomics Gene expression Mitochondria |
| url | http://www.sciencedirect.com/science/article/pii/S2352396417304267 |
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