Associations of Biopterins and ADMA with Vascular Function in Peripheral Microcirculation from Patients with Chronic Kidney Disease

We hypothesized that patients with chronic kidney disease (CKD) display an altered plasma amino acid (AA) metabolomic profile that could contribute to abnormal vascular maintenance of peripheral circulation in uremia. The relationships between plasma AAs and endothelial and vascular smooth muscle function in the microcirculation of CKD patients are not well understood. The objective of this study is to investigate to what extent the levels of AAs and its metabolites are changed in CKD patients and to test their relationship with endothelial and vascular smooth muscle function. Patients with CKD stages 3 and 5 and non-CKD controls are included in this study. We report that there was a significant reduction of the biopterin (BH4/BH2) ratio, which was accompanied by increased plasma levels of BH2, asymmetric dimethylarginine (ADMA) and citrulline in patients with CKD-5 vs. CKD-3 vs. controls. In vivo augmentation index measurement showed a positive association with ADMA in all participants. The contribution of nitric oxide, assessed by ex vivo assay, showed a negative association with creatinine, ADMA and citrulline in all participants. In CKD-5, BH4 negatively correlated with ADMA and ornithine levels, and the ex vivo endothelium-mediated dilatation positively correlated with phenylalanine levels. In conclusion, uremia is associated with alterations in AA metabolism that may affect endothelium-dependent dilatation and vascular stiffness in microcirculation. Interventional strategies aiming to normalize the AA metabolism could be of interest as treatment options.

[1]  A. Figueroa,et al.  Effects of L-Citrulline Supplementation on Endothelial Function and Blood Pressure in Hypertensive Postmenopausal Women , 2022, Nutrients.

[2]  Meng Li,et al.  The Role of Amino Acids in Endothelial Biology and Function , 2022, Cells.

[3]  C. Kovesdy.  Epidemiology of chronic kidney disease: an update 2022. , 2022, Kidney international supplements.

[4]  Jianping Cao,et al.  The Critical Role of Tetrahydrobiopterin (BH4) Metabolism in Modulating Radiosensitivity: BH4/NOS Axis as an Angel or a Devil , 2021, Frontiers in Oncology.

[5]  Chen Zhang,et al.  L-phenylalanine attenuates high salt-induced hypertension in Dahl SS rats through activation of GCH1-BH4 , 2021, PloS one.

[6]  Amit J. Shah,et al.  Impaired Peripheral Microvascular Function and Risk of Major Adverse Cardiovascular Events in Patients With Coronary Artery Disease , 2021, Arteriosclerosis, thrombosis, and vascular biology.

[7]  D. Fliser,et al.  Cardiovascular Disease in Chronic Kidney Disease , 2021, Circulation.

[8]  C. Zoccali,et al.  Endothelial Dysfunction in Chronic Kidney Disease, from Biology to Clinical Outcomes: A 2020 Update , 2020, Journal of clinical medicine.

[9]  P. Campiglia,et al.  Inflammation and Oxidative Stress in Chronic Kidney Disease—Potential Therapeutic Role of Minerals, Vitamins and Plant-Derived Metabolites , 2019, International journal of molecular sciences.

[10]  E. Karna,et al.  Proline-dependent regulation of collagen metabolism , 2019, Cellular and Molecular Life Sciences.

[11]  J. Burgerhof,et al.  The Effect of Various Doses of Phenylalanine Supplementation on Blood Phenylalanine and Tyrosine Concentrations in Tyrosinemia Type 1 Patients , 2019, Nutrients.

[12]  V. Liakopoulos,et al.  Oxidative Stress in the Pathogenesis and Evolution of Chronic Kidney Disease: Untangling Ariadne’s Thread , 2019, International journal of molecular sciences.

[13]  J. Rodriguez-Perez,et al.  Asymmetric (ADMA) and Symmetric (SDMA) Dimethylarginines in Chronic Kidney Disease: A Clinical Approach , 2019, International journal of molecular sciences.

[14]  J. Phang,et al.  Proline Metabolism in Cell Regulation and Cancer Biology: Recent Advances and Hypotheses , 2017, Antioxidants & redox signaling.

[15]  Xin Xu,et al.  Asymmetric dimethylarginine (ADMA) as an important risk factor for the increased cardiovascular diseases and heart failure in chronic kidney disease. , 2018, Nitric oxide : biology and chemistry.

[16]  R. Soheilifard,et al.  Mechanical elasticity of proline-rich and hydroxyproline-rich collagen-like triple-helices studied using steered molecular dynamics. , 2018, Journal of the mechanical behavior of biomedical materials.

[17]  L. Dailey,et al.  l-Phenylalanine Restores Vascular Function in Spontaneously Hypertensive Rats Through Activation of the GCH1-GFRP Complex , 2018, JACC. Basic to translational science.

[18]  Yan Li,et al.  A novel and reliable method for tetrahydrobiopterin quantification: Benzoyl chloride derivatization coupled with liquid chromatography‐tandem mass spectrometry analysis , 2018, Free radical biology & medicine.

[19]  D. Galvan,et al.  The hallmarks of mitochondrial dysfunction in chronic kidney disease. , 2017, Kidney international.

[20]  K. Denton,et al.  Renal Nitric Oxide Deficiency and Chronic Kidney Disease in Young Sheep Born with a Solitary Functioning Kidney , 2016, Scientific Reports.

[21]  M. Goligorsky.  Pathogenesis of endothelial cell dysfunction in chronic kidney disease: a retrospective and what the future may hold , 2015, Kidney research and clinical practice.

[22]  V. Sivakumar,et al.  Nitric oxide status in patients with chronic kidney disease , 2014, Indian journal of nephrology.

[23]  G. Douglas,et al.  Tetrahydrobiopterin in cardiovascular health and disease. , 2014, Antioxidants & redox signaling.

[24]  J. Rácek,et al.  Asymmetric Dimethylarginine and Progression of Chronic Kidney Disease - a One-Year Follow-Up Study , 2014, Kidney and Blood Pressure Research.

[25]  H. Mischak,et al.  Plasma and urinary amino acid metabolomic profiling in patients with different levels of kidney function. , 2014, Clinical journal of the American Society of Nephrology : CJASN.

[26]  U. Förstermann,et al.  Nitric oxide synthases: regulation and function. , 2012, European heart journal.

[27]  F. Arigoni,et al.  Effect of oral L-arginine supplementation on blood pressure: a meta-analysis of randomized, double-blind, placebo-controlled trials. , 2011, American heart journal.

[28]  M. Crabtree,et al.  Synthesis and recycling of tetrahydrobiopterin in endothelial function and vascular disease. , 2011, Nitric oxide : biology and chemistry.

[29]  C. Zoccali,et al.  Inflammation and asymmetric dimethylarginine for predicting death and cardiovascular events in ESRD patients. , 2011, Clinical journal of the American Society of Nephrology : CJASN.

[30]  J. Carrero,et al.  Impaired resistance artery function in patients with end-stage renal disease. , 2011, Clinical science.

[31]  E. Werner,et al.  Tetrahydrobiopterin protects the kidney from ischemia-reperfusion injury. , 2010, Kidney international.

[32]  D. Harrison,et al.  GTP Cyclohydrolase I Phosphorylation and Interaction With GTP Cyclohydrolase Feedback Regulatory Protein Provide Novel Regulation of Endothelial Tetrahydrobiopterin and Nitric Oxide , 2010, Circulation research.

[33]  A. Hale,et al.  Critical Role for Tetrahydrobiopterin Recycling by Dihydrofolate Reductase in Regulation of Endothelial Nitric-oxide Synthase Coupling , 2009, The Journal of Biological Chemistry.

[34]  S. Agewall,et al.  Endothelium-derived hyperpolarizing factor in vascular physiology and cardiovascular disease. , 2009, Atherosclerosis.

[35]  D. Fekkes,et al.  Quantitation of total biopterin and tetrahydrobiopterin in plasma. , 2007, Clinical biochemistry.

[36]  Frank Donnerstag,et al.  ADMA Increases Arterial Stiffness and Decreases Cerebral Blood Flow in Humans , 2006, Stroke.

[37]  Hyung-Suk Kim,et al.  Amino acids as modulators of endothelium-derived nitric oxide. , 2006, American journal of physiology. Renal physiology.

[38]  Amir Lerman,et al.  Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. , 2004, Journal of the American College of Cardiology.

[39]  M. Brin,et al.  Phenylalanine loading as a diagnostic test for DRD: interpreting the utility of the test. , 2004, Molecular genetics and metabolism.

[40]  C. Zoccali,et al.  Analysis of the relationship between norepinephrine and asymmetric dimethyl arginine levels among patients with end-stage renal disease. , 2004, Journal of the American Society of Nephrology : JASN.

[41]  R. Saunders-Pullmana,et al.  Phenylalanine loading as a diagnostic test for DRD : interpreting the utility of the test , 2004 .

[42]  C. Zoccali,et al.  Left ventricular hypertrophy, cardiac remodeling and asymmetric dimethylarginine (ADMA) in hemodialysis patients. , 2002, Kidney international.

[43]  T. Hosoya,et al.  Plasma pteridine concentrations in patients with chronic renal failure. , 2002, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[44]  C. Zoccali,et al.  Asymmetric dimethylarginine, C-reactive protein, and carotid intima-media thickness in end-stage renal disease. , 2002, Journal of the American Society of Nephrology : JASN.

[45]  Tanaka.  The role of , 2000, Journal of insect physiology.

[46]  R. D'Hooge,et al.  Consequences of renal mass reduction on amino acid and biogenic amine levels in nephrectomized mice , 2000, Amino Acids.

[47]  E. Werner,et al.  Biosynthesis of nitric oxide: dependence on pteridine metabolism. , 1996, Reviews of physiology, biochemistry and pharmacology.

[48]  S. Moncada,et al.  Effect of local intra-arterial asymmetric dimethylarginine (ADMA) on the forearm arteriolar bed of healthy volunteers. , 1993, Journal of human hypertension.