Characterization of the Intrarenal Renin-Angiotensin System in Experimental Alport Syndrome
Characterization of the Intrarenal Renin-Angiotensin System in Experimental Alport Syndrome
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DOI：
10.1016/j.ajpath.2015.01.021
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发表时间：
2015-05-01
影响因子：
6
通讯作者：
Scholey, James W.
中科院分区：
文献类型：
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作者：
Bae, Eun Hui;Konvalinka, Ana;Scholey, James W.
阻断肾素-血管紧张素系统可减缓实验性和临床Alport综合征（AS）的进展;然而，其潜在机制尚不清楚。我们评估了4周龄和7周龄胶原蛋白IV型α 3基因纯合子（Col 4A 3（-/-））和野生型小鼠的肾素-血管紧张素系统，AS模型的特征是蛋白尿和进行性肾损伤。与年龄匹配的对照组相比，7周龄Col 4a 3（-/-）小鼠的肾脏血管紧张素（Ang）II水平升高，而肾脏Ang-（1-7）水平降低;这些变化被重组血管紧张素转换酶2（ACE 2）治疗部分逆转。与野生型小鼠相比，Col 4a 3（-/-）中血管紧张素原和肾素蛋白的表达均增加。与Ang-（1-7）水平一致，7周龄Col 4a 3（-/-）小鼠肾脏ACE 2的表达和活性降低。ACE 2的尿排泄率随组织表达的下降而下降。通过微阵列分析，与野生型小鼠相比，7周龄Col 4a 3（-/-）小鼠肾脏中血管紧张素II诱导基因血红素加氧酶-1的表达上调。血红素氧合酶-1（HO-1）蛋白表达在Col 4a 3（-/-）小鼠肾脏中增加，并通过ACE抑制剂治疗恢复正常。尿HO-1排泄与肾HO-1表达相关。总之，AS进行性肾损伤与肾内肾素-血管紧张素系统组分和血管紧张素肽表达的变化有关。HO-1和ACE 2可能代表AS相关肾损伤的新标志物，而重组ACE 2和/或Ang-（1-7）的给药可能代表AS的新治疗方法。
Blockade of the renin-angiotensin system attenuates the progression of experimental and clinical Alport syndrome (AS); however, the underlying mechanism(s) remains Largely unknown. We evaluated the renin-angiotensin system in 4- and 7-week-old homozygous for collagen, type IV, alpha 3 gene (Col4A3(-/-)) and wild-type mice, a model of AS characterized by proteinuria and progressive renal injury. Renal angiotensin (Ang) II levels increased, whereas renal Ang-(1-7) levels decreased in 7-week-old Col4a3(-/-) mice compared with age-matched controls; these changes were partially reversed by recombinant angiotensin-converting enzyme 2 (ACE2) treatment. The expression of both the angiotensinogen and renin protein increased in Col4a3(-/-) compared with wild-type mice. Consistent with the Ang-(1-7) levels, the expression and activity of kidney ACE2 decreased in 7-week-old Col4a3(-/-) mice. The urinary excretion rate of ACE2 paralleled the decline in tissue expression. Expression of an Ang II-induced gene, heme oxygenase-1, was up-regulated in the kidneys of 7-week-old Col4a3(-/-) mice compared with wild-type mice by microarray analysis. Heme oxygenase-1 (HO-1) protein expression was increased in kidneys of Col4a3(-/-) mice and normalized by treatment with ACE inhibitor. Urinary HO-1 excretion paralleled renal HO-1 expression. In conclusion, progressive kidney injury in AS is associated with changes in expression of intrarenal renin Ang system components and Ang peptides. HO-1 and ACE2 may represent novel markers of AS-associated kidney injury, whereas administration of recombinant ACE2 and/or Ang-(1-7) may represent novel therapeutic approaches in AS.