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The role of asymmetric and symmetric dimethylarginines in renal disease

Nature Reviews Nephrology volume 7, pages 275–285 (2011)Cite this article

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Abstract

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases. By inhibiting nitric oxide formation, ADMA causes endothelial dysfunction, vasoconstriction, elevation of blood pressure, and aggravation of experimental atherosclerosis. Levels of ADMA and its isomer symmetric dimethylarginine (SDMA), which does not inhibit nitric oxide synthesis, are both elevated in patients with kidney disease. Currently available data from prospective clinical trials in patients with chronic kidney disease suggest that ADMA is an independent marker of progression of renal dysfunction, vascular complications and death. High SDMA levels also negatively affect survival in populations at increased cardiovascular risk, but the mechanisms underlying this effect are currently only partly understood. Beyond glomerular filtration, other factors influence the plasma concentrations of ADMA and SDMA. Elevated plasma concentrations of these dimethylarginines might also indirectly influence the activity of nitric oxide synthases by inhibiting the uptake of cellular L-arginine. Other mechanisms may exist by which SDMA exerts its biological activity. The biochemical pathways that regulate ADMA and SDMA, and the pathways that transduce their biological function, could be targeted to treat renal disease in the future.

Key Points

  • Circulating levels of asymmetric dimethylarginine (ADMA) are regulated by its release from methylated proteins, glomerular filtration, and enzymatic degradation by dimethylarginine dimethylaminohydrolase (DDAH)

  • In patients with renal diseases, the loss of DDAH activity contributes more to elevated ADMA concentrations than does reduced glomerular filtration

  • ADMA levels are a predictor of all-cause mortality, major cardiovascular and cerebrovascular events, and progression of renal disease

  • Symmetric dimethylarginine (SDMA) is more abundant than ADMA in patients with chronic kidney disease

  • SDMA has emerged as an endogenous marker of renal function, as its levels are closely related to glomerular filtration rate

  • SDMA has been viewed as a biologically inert molecule; however, strong evidence now indicates a role for both ADMA and SDMA in cardiovascular and cerebrovascular diseases

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Figure 1: Schematic representation of pathways related to methylarginine biosynthesis and metabolism.
Figure 2: Pathological and physiological events that lead to elevated ADMA levels in patients with renal disease.
Figure 3: Results of prospective clinical trials that assessed ADMA levels in patients with renal diseases.
Figure 4: Pathological and physiological mechanisms underlying the associations between levels of dimethylarginines and both vascular injury and renal disease.

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Acknowledgements

Some of the authors' studies cited in this article were funded by the Deutsche Forschungsgemeinschat (Grants Bo 1431/3-1 and Bo 1431/4-1).

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  1. Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Martinistrasse 52, 20246, Hamburg, Germany

    Edzard Schwedhelm & Rainer H. Böger

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  1. Edzard Schwedhelm
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Both authors contributed equally to writing, discussing content and reviewing/editing the manuscript before submission. E. Schwedhelm researched data for this article.

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Correspondence to Rainer H. Böger.

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E. Schwedhelm and R. H. Böger declare that they are patent holders with the University of Hamburg, Germany. R. H. Böger declares that he is a stock holder/director with GermedIQ GmbH.

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Schwedhelm, E., Böger, R. The role of asymmetric and symmetric dimethylarginines in renal disease. Nat Rev Nephrol 7, 275–285 (2011). https://doi.org/10.1038/nrneph.2011.31

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