Role of asymmetric dimethylarginine in cardio-renal syndrome

不对称二甲基精氨酸在心肾综合征中的作用

• 批准号: 20590969
• 负责人: UEDA Seiji
• 金额: $ 3万
• 依托单位: Kurume University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20590969/
• 关键词: 慢性腎臓病; 心腎連関; 酸化ストレス; ADMA; 血管内皮障害; 糸球体硬化; 間質線維化; 小胞体ストレス; 蛋白尿; 心肥大; 内皮障害

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.

近年来，越来越多的证据表明，慢性肾脏疾病（CKD）是强大的心血管危险因素，因此，概念“心脏 - 肾脏综合征（CRS）”众所周知。可以解释这种联系的一个可能因素似乎是内皮功能障碍（ED），它在动脉粥样硬化的起始和进展中起重要作用以及CKD的进展。在这项研究中，我们研究了不对称二甲基精氨酸（ADMA）的作用，这是CRS中ED的原因。在CKD患者中，随着CKD期的进展，血浆ADMA水平升高。此外，ADMA水平升高与PWV和LV质量指数，这些患者心血管疾病的替代标记显着相关。此外，ADMA水平与肾小球硬化和间质纤维化的程度以及GFR的年度降低率显着相关。 CKD的动物模型表明，DDAH的氧化应激和/或ER应力介导的失调，ADMA的酶可以解释CKD中的ADMA升高。 CKD模型中DDAH基因转移的ADMA水平降低不仅可以改善ED，而且阻止了肾脏损伤的发展。 ADMA是一种有效的内源性NOS抑制剂，其积累可能在ED中起重要作用，从而有助于CKD患者的心血管疾病和肾脏损伤的发展和进展。通过增强DDAH活性来抵抗ADMA可能是新型策略，也可以防止CKD患者的心脏并发症。

项目成果

Involvement of asymmetric dimethylarginine (ADMA) tubulointerstitial ischemia in early phase of diabetic nephropathy.

糖尿病肾病早期不对称二甲基精氨酸（ADMA）肾小管间质缺血的参与。

• 发表时间: 2009
• 期刊: Nephrol Dial Transplant. 24
• 作者: Shibata R;Ueda S;et al.
• 通讯作者: et al.

Ezetimibe decrease serum levels of asymmetric dimethylarginine (ADMA) and ameliorates renal injury in non-diabetic chronic kidney disease patients in a cholesterol-independent manner.

依泽替米贝以不依赖胆固醇的方式降低非对称二甲基精氨酸 (ADMA) 的血清水平并改善非糖尿病慢性肾病患者的肾损伤。

• 发表时间: 2009
• 期刊: Pharmacol Res. 60
• 作者: Nakamura T;Sata E;Fujiwara N;Kawagoe Y;Suzuki T;Ueda Y;Ueda S;Adachi H;Okuda S;Yamagishi S.
• 通讯作者: Yamagishi S.

心腎連関とADMA

心肾连接和 ADMA

• 发表时间: 2010
• 作者: Takabatake Y;et al.;Huang Y;上田誠二;Ichida K;上田誠二
• 通讯作者: 上田誠二

New pathways to renal damage : Role of ADMA for retarding renal disease progression

肾损伤的新途径：ADMA 在延缓肾病进展中的作用

• 发表时间: 2010
• 期刊: J Nephrol. (In press)
• 作者: Ueda S;Yamagishi S;Okuda S.
• 通讯作者: Okuda S.

Cell Growth Processes : New Research. Implication of asymmetric dimethylariginine (ADMA) in cell growth process in atherosclerosis

细胞生长过程：新研究。

• 发表时间: 2008
• 作者: Ueda S;et al.
• 通讯作者: et al.