Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle'' region for nonproteolytic activation of prorenin
Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle'' region for nonproteolytic activation of prorenin
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DOI：
10.1172/jci200421398
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发表时间：
2004-10-01
影响因子：
15.9
通讯作者：
Saruta, T
中科院分区：
文献类型：
--
作者：
Ichihara, A;Hayashi, M;Saruta, T
我们发现，当一个位点特异的结合蛋白与原肾素前段的“手柄”区域相互作用时，原肾素分子经历了构象。改变到其酶活性状态。这种非蛋白水解性激活完全被具有句柄区域结构的诱饵肽所阻断，该诱饵肽竞争性地与这种结合蛋白结合。鉴于糖尿病患者血浆前肾素升高，我们验证了原肾素的非蛋白水解性激活在糖尿病器官损害中起重要作用的假说。给链脲佐菌素诱导的糖尿病大鼠皮下注射手柄区肽。在链脲佐菌素治疗后的8、16和24周，检测代谢和肾脏组织学改变以及血浆和肾脏中肾素-血管紧张素系统的组成。糖尿病大鼠肾脏血管紧张素I和血管紧张素II含量增加，肾素、血管紧张素转换酶或血管紧张素原合成没有任何变化。治疗后肾组织血管紧张素I和血管紧张素II的含量降低，完全抑制糖尿病肾病的发展，但不影响高血糖。我们认为原肾素的非蛋白水解性激活可能是糖尿病肾病的一个重要机制。前列环素非蛋白水解性激活的机制和物质可作为预防糖尿病器官损害的重要治疗靶点。
We found that when a site-specific binding protein interacts with the "handle" region of the prorenin prosegment, the prorenin molecule undergoes a conformational. change to its enzymatically active state. This nonproteolytic activation is completely blocked by a decoy peptide with the handle region structure, which competitively binds to such a binding protein. Given increased plasma prorenin in diabetes, we examined the hypothesis that the nonproteolytic activation of prorenin plays a significant role in diabetic organ damage. Streptozotocin-induced diabetic rats were treated with subcutaneous administration of handle region peptide. Metabolic and renal histological changes and the renin-Ang system components in the plasma and kidneys were determined at 8, 16, and 24 weeks following streptozotocin treatment. Kidneys of diabetic rats contained increased Ang I and II without any changes in renin, Ang-converting enzyme, or angiotensinogen synthesis. Treatment with the handle region peptide decreased the renal content of Ang I and II, however, and completely inhibited the development of diabetic nephropathy without affecting hyperglycemia. We propose that the nonproteolytic activation of prorenin may be a significant mechanism of diabetic nephropathy. The mechanism and substances causing nonproteolytic activation of prorenin may serve as important therapeutic targets for the prevention of diabetic organ damage.