Symmetric dimethylarginine as a proinflammatory agent in chronic kidney disease.

Abstract

BACKGROUND & OBJECTIVES:

Chronic kidney disease (CKD) is characterized by chronic inflammation, considered a nontraditional risk factor for cardiovascular disease, the major cause of death in CKD. Symmetric dimethylarginine (SDMA) was recently demonstrated to induce reactive oxygen species in monocytes. The present study further investigates the inflammatory character of SDMA compared with its structural counterpart asymmetric dimethylarginine (ADMA).

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:

In vitro, the effect of SDMA on intracellular monocytic expression of IL-6 and TNF-α was studied followed by an evaluation of nuclear factor (NF)-κB activation. Additionally, an association of SDMA with inflammatory parameters in consecutive stages of CKD was evaluated in vivo.

RESULTS:

Monocytes incubated with SDMA showed increased IL-6 and TNF-α expression and a rise in active NF-κB. N-acetylcysteine abrogated both these effects. No significant effects were observed with ADMA. In vivo, 142 patients (67 ± 12 years) at different stages of CKD showed an inverse association between serum SDMA and ADMA and renal function. Correlations between SDMA and IL-6, TNF-α, and albumin were more significant than for ADMA, while multiple regression analysis only retained TNF-α at a high significance for SDMA (P < 0.0001). In receiver operating characteristic analysis for inflammation, defined as an IL-6 level above 2.97 pg/ml (median), the discriminative power of SDMA (area under the curve [AUC]: 0.69 ± 0.05) directly followed that of C-reactive protein (AUC: 0.82 ± 0.04) and albumin (AUC: 0.72 ± 0.05; for all, P < 0.0001) and preceded that of ADMA (P = 0.002).

CONCLUSIONS:

The present study shows that SDMA is involved in the inflammatory process of CKD, activating NF-κB and resulting in enhanced expression of IL-6 and TNF-α, which is corroborated by the clinical data pointing to an in vivo association of SDMA with inflammatory markers in CKD at different stages.

• Authors: Eva Schepers, Daniela V Barreto, Sophie Liabeuf, Griet Glorieux, Sunny Eloot, Fellype C Barreto, Ziad Massy, Raymond Vanholder, European Uremic Toxin Work Group (EUTox)
• Journal: Clinical journal of the American Society of Nephrology : CJASN (Clin J Am Soc Nephrol) Vol. 6 Issue 10 Pg. 2374-83 (Oct 2011) ISSN: 1555-905X [Electronic] United States
• PMID: 21817129 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• IL6 protein, human
• Inflammation Mediators
• Interleukin-6
• NF-kappa B
• Tumor Necrosis Factor-alpha
• symmetric dimethylarginine
• N,N-dimethylarginine
• Arginine
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Aged
• Aged, 80 and over
• Arginine (analogs & derivatives, blood, metabolism)
• Belgium
• Biomarkers (metabolism)
• Case-Control Studies
• Cell Line
• Chronic Disease
• Cross-Sectional Studies
• Female
• Humans
• Inflammation Mediators (blood, metabolism)
• Interleukin-6 (metabolism)
• Kidney Diseases (diagnosis, immunology, physiopathology)
• Linear Models
• Male
• Middle Aged
• Monocytes (drug effects, immunology)
• NF-kappa B (metabolism)
• Predictive Value of Tests
• ROC Curve
• Tumor Necrosis Factor-alpha (metabolism)