Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan.
Kidney Int. 2012 Apr;81(8):762-8. doi: 10.1038/ki.2011.476. Epub 2012 Feb 1.
Patients with chronic kidney disease have elevated circulating asymmetric dimethylarginine (ADMA). Recent studies have suggested that ADMA impairs endothelial nitric oxide synthase (eNOS) by effects other than competition with the substrate L-arginine. Here, we sought to identify the molecular mechanism by which increased ADMA causes endothelial dysfunction in a chronic kidney disease model. In wild-type mice with remnant kidney disease, blood urea nitrogen, serum creatinine, and ADMA were increased by 2.5-, 2-, and 1.2-fold, respectively, without any change in blood pressure. Nephrectomy reduced endothelium-dependent relaxation and eNOS phosphorylation at Ser1177 in isolated aortic rings. In transgenic mice overexpressing dimethylarginine dimethylaminohydrolase-1, the enzyme that metabolizes ADMA, circulating ADMA was not increased by nephrectomy and was decreased to half that of wild-type mice. These mice did not exhibit the nephrectomy-induced inhibition of both endothelium-dependent relaxation and eNOS phosphorylation. In cultured human endothelial cells, agonist-induced eNOS phosphorylation and nitric oxide production were decreased by ADMA at concentrations less than that of L-arginine in the media. Thus, elevated circulating ADMA may be a cause, not an epiphenomenon, of endothelial dysfunction in chronic kidney disease. This effect may be attributable to inhibition of eNOS phosphorylation.
患有慢性肾病的患者血液中循环的不对称二甲基精氨酸（ADMA）水平升高。最近的研究表明，ADMA 通过与底物 L-精氨酸竞争以外的其他作用来损害内皮型一氧化氮合酶（eNOS）。在这里，我们试图确定 ADMA 增加导致慢性肾脏病模型中内皮功能障碍的分子机制。在剩余肾疾病的野生型小鼠中，血尿素氮、血清肌酐和 ADMA 分别增加了 2.5 倍、2 倍和 1.2 倍，而血压没有任何变化。肾切除术降低了离体主动脉环中内皮依赖性松弛和 eNOS 丝氨酸 1177 磷酸化。在过表达 ADMA 代谢酶二甲基精氨酸二甲氨基水解酶-1 的转基因小鼠中，肾切除术后循环 ADMA 没有增加，并降低至野生型小鼠的一半。这些小鼠没有表现出肾切除术后内皮依赖性松弛和 eNOS 磷酸化的双重抑制。在培养的人内皮细胞中，与培养基中的 L-精氨酸相比，浓度较低的 ADMA 可降低激动剂诱导的 eNOS 磷酸化和一氧化氮产生。因此，循环 ADMA 升高可能是慢性肾脏病内皮功能障碍的原因，而不是一种现象。这种作用可能归因于 eNOS 磷酸化的抑制。
