Effect of ACE2 and angiotensin-(1-7) in a mouse model of early chronic kidney disease
Effect of ACE2 and angiotensin-(1-7) in a mouse model of early chronic kidney disease
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DOI：
10.1152/ajprenal.00426.2009
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发表时间：
2010-06-01
影响因子：
4.2
通讯作者：
Burns, Kevin D.
中科院分区：
文献类型：
--
作者：
Dilauro, Marc;Zimpelmann, Joseph;Burns, Kevin D.
首页--期刊主要分类--期刊细介绍--期刊题录与文摘-期刊详细文摘内容血管紧张素转换酶2和血管紧张素-(1-7)对早期慢性肾脏病小鼠模型的影响。Am J Physiol Renal Physiol 298：F1523-F1532,2010。Doi:10.1152/ajprenal.00426.2009.-Angiotensin-converting酶2(ACE2)在肾脏高水平表达，可将血管紧张素II(Ang II)转化为Ang-(1-7)。研究血管紧张素转换酶2(ACE2)抑制和血管紧张素-(1-7)(Ang-(1-7))在5/6肾切除(5/6 NX)小鼠慢性肾脏病(CKD)模型中的作用。雄性FVB小鼠分为假手术组(Sham)和5/6NX组，分别给予ACE2抑制剂mln-4760(Mln)、AT(1)受体拮抗剂氯沙坦、mln加氯沙坦或Ang(1-7)治疗4wk。在有无MLN的5/6 NX小鼠中，肾皮质ACE2蛋白的表达在4wk时显著低于Sham。抑制ACE2可导致肾皮质ACE2活性下降。肾皮质血管紧张素转换酶的表达和活性在不同组小鼠之间没有差异。5/6只NX小鼠经MLN治疗后，肾脏血管紧张素Ⅱ水平较假手术组显著升高。5/6NX引起血压(BP)轻度升高，FITC菊粉清除率下降50%，尿白蛋白排泄量显著增加。在5/6 NX小鼠中抑制ACE2并不影响BP或FITC菊粉的清除，但与单独使用5/6 NX相比显著增加蛋白尿，这一作用被氯沙坦逆转。Ang-(1-7)可增加5/6 Nx小鼠肾脏和血浆Ang-(1-7)水平，但不改变BP、FITC菊粉清除率或尿白蛋白排泄量，并增加相对系膜面积。这些数据表明，肾脏ACE2在5/6 NX后早期表达下调。抑制5/6 NX小鼠的ACE2可通过AT1受体依赖机制增加蛋白尿，而不受BP的影响。相反，Ang-(1-7)不影响5/6Nx后的蛋白尿。我们认为内源性ACE2在CKD中具有肾脏保护作用。
Dilauro M, Zimpelmann J, Robertson SJ, Genest D, Burns KD. Effect of ACE2 and angiotensin-(1-7) in a mouse model of early chronic kidney disease. Am J Physiol Renal Physiol 298: F1523-F1532, 2010. First published March 31, 2010; doi:10.1152/ajprenal.00426.2009.-Angiotensin-converting enzyme 2 (ACE2) is expressed at high levels in the kidney and converts angiotensin II (ANG II) to ANG-(1-7). We studied the effects of ACE2 inhibition and ANG-(1-7) in the 5/6 nephrectomy (5/6 Nx) mouse model of chronic kidney disease (CKD). Male FVB mice underwent sham surgery (Sham) or 5/6 Nx and were administered either vehicle, the ACE2 inhibitor MLN-4760 (MLN), the AT(1) receptor antagonist losartan, MLN plus losartan, or ANG( 1-7) for 4 wk. In 5/6 Nx mice with or without MLN, kidney cortical ACE2 protein expression was significantly decreased at 4 wk, compared with Sham. Inhibition of ACE2 caused a decrease in renal cortical ACE2 activity. Kidney cortical ACE expression and activity did not differ between groups of mice. In 5/6 Nx mice treated with MLN, kidney levels of ANG II were significantly increased, compared with Sham. 5/6 Nx induced a mild but insignificant increase in blood pressure (BP), a 50% reduction in FITC-inulin clearance, and a significant increase in urinary albumin excretion. ACE2 inhibition in 5/6 Nx mice did not affect BP or FITC-inulin clearance but significantly increased albuminuria compared with 5/6 Nx alone, an effect reversed by losartan. Treatment of 5/6 Nx mice with ANG-(1-7) increased kidney and plasma levels of ANG-(1-7) but did not alter BP, FITC-inulin clearance, or urinary albumin excretion, and it increased relative mesangial area. These data indicate that kidney ACE2 is downregulated in the early period after 5/6 Nx. Inhibition of ACE2 in 5/6 Nx mice increases albuminuria via an AT1 receptor-dependent mechanism, independent of BP. In contrast, ANG-(1-7) does not affect albuminuria after 5/6 Nx. We propose that endogenous ACE2 is renoprotective in CKD.