Loss of angiotensin-converting enzyme-2 leads to the late development of angiotensin II-dependent glomerulosclerosis.
Loss of angiotensin-converting enzyme-2 leads to the late development of angiotensin II-dependent glomerulosclerosis.
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DOI：
10.2353/ajpath.2006.051091
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发表时间：
2006-06
期刊：
影响因子：
--
通讯作者：
Scholey JW
中科院分区：
文献类型：
--
作者：
Oudit GY;Herzenberg AM;Kassiri Z;Wong D;Reich H;Khokha R;Crackower MA;Backx PH;Penninger JM;Scholey JW
血管紧张素转换酶-2（ACE 2）是一种在肾脏中高度表达的膜结合羧肽酶，是肾素-血管紧张素系统的负调节因子。在这里，我们报告了雄性ACE 2突变（ACE 2 −/y）小鼠肾小球系膜中纤维状胶原的早期积累，随后在12个月龄时发生肾小球硬化，而雌性ACE 2突变（ACE 2 −/−）小鼠相对受到保护。与年龄匹配的对照小鼠相比，进行性肾损伤与肾小球中I型胶原、III型胶原和纤连蛋白沉积增加以及尿白蛋白排泄增加相关。血管紧张素II 1型受体拮抗剂厄贝沙坦治疗可预防雄性ACE 2突变小鼠肾小球的这些结构和功能变化。ACE 2的丢失与肾脂质过氧化产物形成和肾小球中丝裂原活化蛋白激酶和细胞外信号调节激酶1和2的活化显著增加相关，这些事件也可通过血管紧张素II 1型受体阻断剂预防。我们的结论是，ACE 2基因的缺失导致血管紧张素II依赖性肾小球损伤的雄性小鼠的发展。这些发现对于我们理解ACE 2、肾素-血管紧张素系统和肾损伤中的性别具有重要意义，ACE 2可能是肾脏疾病的重要治疗靶点。
Angiotensin-converting enzyme-2 (ACE2), a membrane-bound carboxymonopeptidase highly expressed in the kidney, functions as a negative regulator of the renin-angiotensin system. Here we report early accumulation of fibrillar collagen in the glomerular mesangium of male ACE2 mutant (ACE2−/y) mice followed by development of glomerulosclerosis by 12 months of age whereas female ACE2 mutant (ACE2−/−) mice were relatively protected. Progressive kidney injury was associated with increased deposition of collagen I, collagen III and fibronectin in the glomeruli and increased urinary albumin excretion compared to age-matched control mice. These structural and functional changes in the glomeruli of male ACE2 mutant mice were prevented by treatment with the angiotensin II type-1 receptor antagonist irbesartan. Loss of ACE2 was associated with a marked increase in renal lipid peroxidation product formation and activation of mitogen-activated protein kinase and extracellular signal-regulated kinases 1 and 2 in glomeruli, events that are also prevented by angiotensin II type-1 receptor blockade. We conclude that deletion of the ACE2 gene leads to the development of angiotensin II-dependent glomerular injury in male mice. These findings have important implications for our understanding of ACE2, the renin-angiotensin system, and gender in renal injury, with ACE2 likely to be an important therapeutic target in kidney disease.
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影响因子：
4.1
作者：
Gorin, Y;Ricono, JM;Abboud, HE
通讯作者：
Abboud, HE
影响因子：
64.8
作者：
Li W;Moore MJ;Vasilieva N;Sui J;Wong SK;Berne MA;Somasundaran M;Sullivan JL;Luzuriaga K;Greenough TC;Choe H;Farzan M
通讯作者：
Farzan M
影响因子：
8.3
作者：
Border, WA;Noble, NA
通讯作者：
Noble, NA
影响因子：
56.9
作者：
Lee, SH;Oe, T;Blair, IA
通讯作者：
Blair, IA
影响因子：
15.9
作者：
KAGAMI, S;BORDER, WA;NOBLE, NA
通讯作者：
NOBLE, NA