Role of asymmetric dimethylarginine in cardio-renal syndrome

近年来，越来越多的证据表明，慢性肾脏病（CKD）是一个强大的心血管危险因素，因此，“肾脏综合征（CRS）”的概念是众所周知的。一个可能的因素，可以解释这种联系似乎是内皮功能障碍（艾德），它在动脉粥样硬化的起始和进展以及CKD的进展中起着重要作用。在这项研究中，我们调查的作用，不对称二甲基精氨酸（ADMA），艾德在CRS的致病因素。在CKD患者中，血浆ADMA水平随着CKD分期的进展而升高。此外，ADMA水平升高与PWV和LV质量指数显著相关，PWV和LV质量指数是这些患者心血管疾病的替代标志物。此外，ADMA水平与肾小球硬化和间质纤维化程度以及活检证实的慢性肾小球肾炎患者的GFR年下降率显著相关。CKD动物模型显示，氧化应激和/或ER应激介导的DDAH（ADMA的一种酶）调节异常可解释CKD中ADMA升高。通过DDAH基因转移降低CKD模型中ADMA水平不仅改善了艾德，而且阻断了肾损伤的发展。ADMA是一种有效的内源性NOS抑制剂，其蓄积可能在艾德性ED中发挥重要作用，从而促进CKD患者心血管疾病和肾损伤的发生和进展。通过增强DDAH活性对抗ADMA可能是预防CKD患者心肾并发症的新策略。

In recent years, increasing evidence has been shown that chronic kidney disease (CKD) is a strong cardiovascular risk factor, and therefore, the concept 'Cardio-Renal Syndrome (CRS)' is well recognized. One possible factor that could explain this link seems to be endothelial dysfunction (ED), which plays important roles in initiation and progression of atherosclerosis as well as progression of CKD. In this study, we investigated the roles of asymmetric dimethylarginine (ADMA), a causative factor for ED in CRS. In CKD patients, plasma levels of ADMA were increased as CKD stage progressed. Further, increased ADMA levels were significantly associated with PWV and LV mass index, surrogate markers for cardiovascular disease in these patients. In addition, ADMA levels were significantly related to the degree of glomerulosclerosis and interstitial fibrosis as well as annual reduction rates of GFR in biopsy-proven chronic glomerulonephritis patients. Animal models of CKD revealed that oxidative stress and/or ER stress-mediated dysregulation of DDAH, an enzyme for ADMA could account for ADMA elevation in CKD. Reduction of ADMA levels by DDAH gene transfer in CKD models not only ameliorated ED but also blocked the development of renal injury. ADMA is a potent endogenous NOS inhibitor and its accumulation may play important roles in ED, thereby contributing to the development and progression of cardiovascular disease and renal injury in patients with CKD. Countering of ADMA by enhancement of DDAH activity may be novel strategies or preventing the cardiorenal complications in patients with CKD.