| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2010: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2009: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Research Abstract |
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.
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