Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Diabetes. 2010 Feb;59(2):529-38. doi: 10.2337/db09-1218. Epub 2009 Nov 23.
Diabetic nephropathy is one of the most common causes of end-stage renal failure. Inhibition of ACE2 function accelerates diabetic kidney injury, whereas renal ACE2 is downregulated in diabetic nephropathy. We examined the ability of human recombinant ACE2 (hrACE2) to slow the progression of diabetic kidney injury.
Male 12-week-old diabetic Akita mice (Ins2(WT/C96Y)) and control C57BL/6J mice (Ins2(WT/WT)) were injected daily with placebo or with rhACE2 (2 mg/kg, i.p.) for 4 weeks. Albumin excretion, gene expression, histomorphometry, NADPH oxidase activity, and peptide levels were examined. The effect of hrACE2 on high glucose and angiotensin II (ANG II)-induced changes was also examined in cultured mesangial cells.
Treatment with hrACE2 increased plasma ACE2 activity, normalized blood pressure, and reduced the urinary albumin excretion in Akita Ins2(WT/C96Y) mice in association with a decreased glomerular mesangial matrix expansion and normalization of increased alpha-smooth muscle actin and collagen III expression. Human recombinant ACE2 increased ANG 1-7 levels, lowered ANG II levels, and reduced NADPH oxidase activity. mRNA levels for p47(phox) and NOX2 and protein levels for protein kinase Calpha (PKCalpha) and PKCbeta1 were also normalized by treatment with hrACE2. In vitro, hrACE2 attenuated both high glucose and ANG II-induced oxidative stress and NADPH oxidase activity.
Treatment with hrACE2 attenuates diabetic kidney injury in the Akita mouse in association with a reduction in blood pressure and a decrease in NADPH oxidase activity. In vitro studies show that the protective effect of hrACE2 is due to reduction in ANG II and an increase in ANG 1-7 signaling.
糖尿病肾病是终末期肾衰竭的最常见原因之一。ACE2 功能的抑制会加速糖尿病肾病损伤，而糖尿病肾病中肾脏 ACE2 下调。我们研究了人重组 ACE2（hrACE2）减缓糖尿病肾病损伤进展的能力。
12 周龄雄性糖尿病 Akita 小鼠（Ins2（WT/C96Y））和对照 C57BL/6J 小鼠（Ins2（WT/WT））每天接受安慰剂或 rhACE2（2mg/kg，腹腔注射）治疗 4 周。检测白蛋白排泄、基因表达、组织形态计量学、NADPH 氧化酶活性和肽水平。还研究了 hrACE2 对高糖和血管紧张素 II（ANG II）诱导的变化的影响在培养的系膜细胞中。
hrACE2 治疗增加了血浆 ACE2 活性，使血压正常，并降低了 Akita Ins2（WT/C96Y）小鼠的尿白蛋白排泄，同时减少肾小球系膜基质扩张，并使增加的α-平滑肌肌动蛋白和胶原 III 表达正常化。人重组 ACE2 增加了 ANG 1-7 水平，降低了 ANG II 水平，并降低了 NADPH 氧化酶活性。hrACE2 还使 p47(phox)和 NOX2 的 mRNA 水平以及蛋白激酶 Calpha（PKCalpha）和 PKCbeta1 的蛋白水平正常化。在体外，hrACE2 减轻了高糖和 ANG II 诱导的氧化应激和 NADPH 氧化酶活性。
hrACE2 治疗减轻了 Akita 小鼠的糖尿病肾病损伤，同时降低了血压并减少了 NADPH 氧化酶活性。体外研究表明，hrACE2 的保护作用归因于 ANG II 的减少和 ANG 1-7 信号的增加。
