Blood content of asymmetric dimethylarginine: new insights into its dysregulation in renal disease.
Blood content of asymmetric dimethylarginine: new insights into its dysregulation in renal disease.
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DOI：
10.1093/ndt/gfn500
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发表时间：
2008-11
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影响因子：
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通讯作者：
S. Billecke;L. D'alecy;Raylene Platel;S. Whitesall;K. Jamerson;R. Perlman;C. Gadegbeku
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文献类型：
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作者：
S. Billecke;L. D'alecy;Raylene Platel;S. Whitesall;K. Jamerson;R. Perlman;C. Gadegbeku
背景技术血浆不对称二甲基精氨酸（ADMA）是一氧化氮合酶的内源性抑制剂，在肾病患者中显着升高，是心血管疾病的潜在危险因素。在这里，我们测试了人类全血 (WB) 是否与啮齿动物血液一样可以积累游离 ADMA，以及这种积累是否是疾病负担的函数。方法 在 16 名健康对照受试者 (CO)、18 名 ESRD 患者和 18 名肾功能正常的高血压患者 (HTN) 中，我们使用高压液相色谱基线血浆和 WB 上清液 (WBSUP) 比较了 5 小时孵育期间 ADMA 和对称二甲基精氨酸 (SDMA) 的浓度和积累。我们测量了孵育的 WBSUP 中的蛋白质周转率，以确定蛋白水解过程是否驱动 ADMA 积累。结果 ESRD 和 HTN 人群血浆 ADMA 升高，而 ESRD 受试者的基础 WBSUP ADMA 显着高于对照组（与 CO 相比，P = 0.05；与 HTN 相比，P = 0.02）。 Plasma SDMA 也遵循类似的模式。 WBSUP 的孵育导致 ADMA 从蛋白质掺入库中释放，而 SDMA 不受影响。 ESRD 样本中的 ADMA 累积量显着高于 HTN 样本中的 ADMA 累积量 (P = 0.03)。 CO 和 HTN 男性的 ADMA 积累显着高于女性（分别为 P = 0.01 和 P = 0.003），但 ESRD 组中未观察到性别差异（P = 0.26）。 ADMA 积累与离体蛋白质周转相关（R = 0.76，P < 0.0001）。结论 人血能够通过蛋白水解途径释放生理学上显着量的 ADMA。 WB 储存库中 ADMA 释放失调可能导致 ESRD 人群血浆 ADMA 水平明显升高。
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.