NDT Advance Access originally published online on September 15, 2008
Nephrology Dialysis Transplantation 2009 24(2):489-496; doi:10.1093/ndt/gfn500
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Blood content of asymmetric dimethylarginine: new insights into its dysregulation in renal disease
1 Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109 2 Department of Surgery, William Beaumont Hospital, Royal Oak, MI 48073 3 Department of Internal Medicine, Wayne State University, Detroit 4 Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Correspondence and offprint requests to: Crystal A. Gadegbeku, University of Michigan Medical School, Simpson Memorial Institute, Rm 310, 102 Observatory Road, Ann Arbor, MI 48109-5725, USA. Tel: +1-734-615-3994; Fax: +1-734-615-4887; E-mail: cgadegbe{at}umich.edu
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Abstract |
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Background. Plasma asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is significantly elevated in patients with kidney disease and is a potential risk factor for cardiovascular disease. Here, we tested whether human whole blood (WB), as in rodent blood, can accumulate free ADMA and whether this accumulation is a function of disease burden.
Methods. In 16 healthy control subjects (CO), 18 patients with ESRD and 18 matched hypertensive patients with normal renal function (HTN), we compared using high-pressure liquid chromatography baseline plasma and WB supernatant (WBSUP) ADMA and symmetrical dimethylarginine (SDMA) concentrations and accumulation during a 5-h incubation. We measured protein turnover in incubated WBSUP to determine if proteolytic processes drive ADMA accumulation.
Results. Elevated plasma ADMA was confirmed in ESRD and HTN populations while basal WBSUP ADMA was significantly higher in ESRD subjects than controls (P = 0.05 versus CO; P = 0.02 versus HTN). Plasma SDMA followed a similar pattern. Incubation of WBSUP resulted in ADMA release from protein-incorporated stores while SDMA was unaffected. ADMA accumulation in ESRD samples was significantly greater than that in HTN (P = 0.03). CO and HTN men showed significantly greater ADMA accumulation than women (P = 0.01 and P = 0.003, respectively) but no gender difference was observed in the ESRD group (P = 0.26). ADMA accumulation correlated with ex vivo protein turnover (R = 0.76, P < 0.0001).
Conclusions. Human blood is capable of releasing physiologically significant quantities of ADMA via proteolytic pathways. Dysregulated ADMA release from WB reservoirs may contribute to the distinctly high plasma ADMA levels in ESRD populations.
Keywords: asymmetric dimethylarginine; cardiovascular risk; end-stage renal disease; symmetric dimethylarginine; whole blood
Received for publication: 25. 4.08
Accepted in revised form: 11. 8.08