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Gene Expression Studies and Targeted Metabolomics Reveal Disturbed Serine, Methionine, and Tyrosine Metabolism in Early Hypertensive Nephrosclerosis

INTRODUCTION: Hypertensive nephrosclerosis is among the leading causes of end-stage renal disease, but its pathophysiology is poorly understood. We wanted to explore early metabolic changes using gene expression and targeted metabolomics analysis. METHODS: We analyzed gene expression in kidneys biop...

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Autores principales: Øvrehus, Marius A., Bruheim, Per, Ju, Wenjun, Zelnick, Leila R., Langlo, Knut A., Sharma, Kumar, de Boer, Ian H., Hallan, Stein I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365407/
https://www.ncbi.nlm.nih.gov/pubmed/30775629
http://dx.doi.org/10.1016/j.ekir.2018.10.007
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author Øvrehus, Marius A.
Bruheim, Per
Ju, Wenjun
Zelnick, Leila R.
Langlo, Knut A.
Sharma, Kumar
de Boer, Ian H.
Hallan, Stein I.
author_facet Øvrehus, Marius A.
Bruheim, Per
Ju, Wenjun
Zelnick, Leila R.
Langlo, Knut A.
Sharma, Kumar
de Boer, Ian H.
Hallan, Stein I.
author_sort Øvrehus, Marius A.
collection PubMed
description INTRODUCTION: Hypertensive nephrosclerosis is among the leading causes of end-stage renal disease, but its pathophysiology is poorly understood. We wanted to explore early metabolic changes using gene expression and targeted metabolomics analysis. METHODS: We analyzed gene expression in kidneys biopsied from 20 patients with nephrosclerosis and 31 healthy controls with an Affymetrix array. Thirty-one amino acids were measured by liquid chromatography coupled with mass spectrometry (LC-MS) in urine samples from 62 patients with clinical hypertensive nephrosclerosis and 33 age- and sex-matched healthy controls, and major findings were confirmed in an independent cohort of 45 cases and 15 controls. RESULTS: Amino acid catabolism and synthesis were strongly underexpressed in hypertensive nephrosclerosis (13- and 7-fold, respectively), and these patients also showed gene expression patterns indicating decreased fatty acid oxidation (12-fold) and increased interferon gamma (10-fold) and cellular defense response (8-fold). Metabolomics analysis revealed significant distribution differences in 11 amino acids in hypertensive nephrosclerosis, among them tyrosine, phenylalanine, dopamine, homocysteine, and serine, with 30% to 70% lower urine excretion. These findings were replicated in the independent cohort. Integrated gene-metabolite pathway analysis showed perturbations of renal dopamine biosynthesis. There were also significant differences in homocysteine/methionine homeostasis and the serine pathway, which have strong influence on 1-carbon metabolism. Several of these disturbances could be interconnected through reduced regeneration of tetrahydrofolate and tetrahydrobiopterin. CONCLUSION: Early hypertensive nephrosclerosis showed perturbations of intrarenal biosynthesis of dopamine, which regulates natriuresis and blood pressure. There were also disturbances in serine/glycine and methionine/homocysteine metabolism, which may contribute to endothelial dysfunction, atherosclerosis, and renal fibrosis.
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spelling pubmed-63654072019-02-15 Gene Expression Studies and Targeted Metabolomics Reveal Disturbed Serine, Methionine, and Tyrosine Metabolism in Early Hypertensive Nephrosclerosis Øvrehus, Marius A. Bruheim, Per Ju, Wenjun Zelnick, Leila R. Langlo, Knut A. Sharma, Kumar de Boer, Ian H. Hallan, Stein I. Kidney Int Rep Translational Research INTRODUCTION: Hypertensive nephrosclerosis is among the leading causes of end-stage renal disease, but its pathophysiology is poorly understood. We wanted to explore early metabolic changes using gene expression and targeted metabolomics analysis. METHODS: We analyzed gene expression in kidneys biopsied from 20 patients with nephrosclerosis and 31 healthy controls with an Affymetrix array. Thirty-one amino acids were measured by liquid chromatography coupled with mass spectrometry (LC-MS) in urine samples from 62 patients with clinical hypertensive nephrosclerosis and 33 age- and sex-matched healthy controls, and major findings were confirmed in an independent cohort of 45 cases and 15 controls. RESULTS: Amino acid catabolism and synthesis were strongly underexpressed in hypertensive nephrosclerosis (13- and 7-fold, respectively), and these patients also showed gene expression patterns indicating decreased fatty acid oxidation (12-fold) and increased interferon gamma (10-fold) and cellular defense response (8-fold). Metabolomics analysis revealed significant distribution differences in 11 amino acids in hypertensive nephrosclerosis, among them tyrosine, phenylalanine, dopamine, homocysteine, and serine, with 30% to 70% lower urine excretion. These findings were replicated in the independent cohort. Integrated gene-metabolite pathway analysis showed perturbations of renal dopamine biosynthesis. There were also significant differences in homocysteine/methionine homeostasis and the serine pathway, which have strong influence on 1-carbon metabolism. Several of these disturbances could be interconnected through reduced regeneration of tetrahydrofolate and tetrahydrobiopterin. CONCLUSION: Early hypertensive nephrosclerosis showed perturbations of intrarenal biosynthesis of dopamine, which regulates natriuresis and blood pressure. There were also disturbances in serine/glycine and methionine/homocysteine metabolism, which may contribute to endothelial dysfunction, atherosclerosis, and renal fibrosis. Elsevier 2018-10-17 /pmc/articles/PMC6365407/ /pubmed/30775629 http://dx.doi.org/10.1016/j.ekir.2018.10.007 Text en © 2018 International Society of Nephrology. Published by Elsevier Inc. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Translational Research
Øvrehus, Marius A.
Bruheim, Per
Ju, Wenjun
Zelnick, Leila R.
Langlo, Knut A.
Sharma, Kumar
de Boer, Ian H.
Hallan, Stein I.
Gene Expression Studies and Targeted Metabolomics Reveal Disturbed Serine, Methionine, and Tyrosine Metabolism in Early Hypertensive Nephrosclerosis
title Gene Expression Studies and Targeted Metabolomics Reveal Disturbed Serine, Methionine, and Tyrosine Metabolism in Early Hypertensive Nephrosclerosis
title_full Gene Expression Studies and Targeted Metabolomics Reveal Disturbed Serine, Methionine, and Tyrosine Metabolism in Early Hypertensive Nephrosclerosis
title_fullStr Gene Expression Studies and Targeted Metabolomics Reveal Disturbed Serine, Methionine, and Tyrosine Metabolism in Early Hypertensive Nephrosclerosis
title_full_unstemmed Gene Expression Studies and Targeted Metabolomics Reveal Disturbed Serine, Methionine, and Tyrosine Metabolism in Early Hypertensive Nephrosclerosis
title_short Gene Expression Studies and Targeted Metabolomics Reveal Disturbed Serine, Methionine, and Tyrosine Metabolism in Early Hypertensive Nephrosclerosis
title_sort gene expression studies and targeted metabolomics reveal disturbed serine, methionine, and tyrosine metabolism in early hypertensive nephrosclerosis
topic Translational Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365407/
https://www.ncbi.nlm.nih.gov/pubmed/30775629
http://dx.doi.org/10.1016/j.ekir.2018.10.007
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