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Methylated Arginines as Biomarkers in Renal Disease

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Biomarkers in Kidney Disease

Abstract

The endogenous methylated analogues of the amino acid arginine, asymmetric dimethylarginine, symmetric dimethylarginine, and monomethylarginine are generated following the degradation of proteins containing methylated arginine residues. Research conducted over the last 25 years has convincingly demonstrated that methylated arginines, in particular asymmetric dimethylarginine and monomethylarginine, play a key role in vascular homeostasis by inhibiting the activity of the three isoforms of nitric oxide synthase, endothelial, neuronal, and inducible, with consequent reduced synthesis of nitric oxide. The increased synthesis and/or reduced catabolism or clearance of methylated arginines might contribute to the onset and progression of endothelial dysfunction, vascular damage, and atherosclerosis through relatively high local exposure in critical organs and tissues. The initial evidence of a detrimental effect of methylated arginines on vascular homeostasis originated from studies in patients with either chronic kidney disease or end-stage renal disease. As the kidney represents a major elimination route, it is not surprising that the plasma/serum concentrations of asymmetric dimethylarginine, symmetric dimethylarginine, and monomethylarginine are significantly increased in patients with renal disease. Methylated arginine concentrations have been shown to independently predict adverse clinical outcomes, e.g., cardiovascular morbidity and mortality and all-cause mortality, both in chronic kidney disease and in end-stage renal disease patients.

This review discusses the synthesis, transport, and elimination of methylated arginines in physiological conditions and their main pathophysiological effects in the cardiovascular system. It also discusses the role of methylated arginines as predictors of adverse outcomes in patients with renal disease and their potential clinical use as biomarkers.

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Abbreviations

ADMA:

Asymmetric dimethylarginine

AQC:

6-Aminoquinolyl-N-hydroxysuccinimidyl carbamate

BNP:

Brain natriuretic peptide

CE:

Capillary electrophoresis

CKD:

Chronic kidney disease

CRP:

C-reactive protein

CVD:

Cardiovascular disease

DAH:

Dialysis-associated hypotension

DMA:

Dimethylamine

ELISA:

Enzyme-linked immunosorbent assay

eNOS:

Endothelial nitric oxide synthase

ESRD:

End-stage renal disease

FITC:

Fluorescein isothiocyanate

FLR:

Fluorescence

GC:

Gas chromatography

HD:

Hemodialysis

HILIC:

Hydrophilic interaction liquid chromatography

HMA:

Homoarginine

HPLC:

High-performance liquid chromatography

LCMS:

Liquid chromatography-mass spectrometry

LDL:

Low-density lipoprotein

LIF:

Laser-induced fluorescence

MI:

Myocardial infarction

MMA:

Monomethylarginine

MRM:

Multiple reaction monitoring

MS:

Mass spectrometry

NDA:

Naphthalene-2,3-dicarboxaldehyde

NO:

Nitric oxide

NOS:

Nitric oxide synthase

OPA:

O-phthaldialdehyde

PFP:

Pentafluoropropionyl

SDMA:

Symmetric dimethylarginine

UPLC:

Ultra-performance liquid chromatography

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Acknowledgments

A Visiting Professorship granted to Professor Mangoni by the Department of Biomedical Sciences, University of Sassari (Italy), facilitated this work.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, School of Medicine, Flinders University, GPO Box 2100, Adelaide, 5001, Australia

    Arduino A. Mangoni & Andrew Rowland

  2. Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100, Sassari, Italy

    Angelo Zinellu, Salvatore Sotgia & Ciriaco Carru

Authors
  1. Arduino A. Mangoni
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  2. Angelo Zinellu
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  3. Salvatore Sotgia
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  4. Andrew Rowland
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  5. Ciriaco Carru
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Corresponding author

Correspondence to Arduino A. Mangoni .

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Editors and Affiliations

  1. DeptofBiomedlSci,FacltyofSci&Technology, University of Westminster , London, United Kingdom

    Vinood B. Patel

  2. Department of Nutrition and Dietetics,Division of Diabetes and Nutritional Sciences, Faculty of Life Science and Medicine, King’s College London, London, United Kingdom

    Victor R. Preedy

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© 2016 Springer Science+Business Media Dordrecht

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Mangoni, A.A., Zinellu, A., Sotgia, S., Rowland, A., Carru, C. (2016). Methylated Arginines as Biomarkers in Renal Disease. In: Patel, V., Preedy, V. (eds) Biomarkers in Kidney Disease. Biomarkers in Disease: Methods, Discoveries and Applications. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7699-9_19

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