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

Marius A Øvrehus; Per Bruheim; Wenjun Ju; Leila R Zelnick; Knut A Langlo; Kumar Sharma; Ian H de Boer; Stein I Hallan

doi:10.1016/j.ekir.2018.10.007

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

Kidney Int Rep. 2018 Oct 17;4(2):321-333. doi: 10.1016/j.ekir.2018.10.007. eCollection 2019 Feb.

Authors

Marius A Øvrehus^{1

2}, Per Bruheim³, Wenjun Ju^{4

5}, Leila R Zelnick^{6

7}, Knut A Langlo², Kumar Sharma⁸, Ian H de Boer^{6

7}, Stein I Hallan^{1

2}

Affiliations

¹ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
² Department of Nephrology, St Olav Hospital, Trondheim University Hospital, Trondheim, Norway.
³ Department of Biotechnology and Food Science, Norwegian University of Science and Technology, Trondheim, Norway.
⁴ Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA.
⁵ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
⁶ Kidney Research Institute, University of Washington, Seattle, Washington, USA.
⁷ Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, USA.
⁸ University of Texas Health San Antonio, San Antonio, Texas, USA.

Abstract

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.

Keywords: amino acids; gene expression; hypertensive nephropathy; metabolomics; nephrosclerosis.

Abstract

Grants and funding