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/jci21398
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发表时间：
2004-10
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通讯作者：
A. Ichihara;M. Hayashi;Y. Kaneshiro;F. Suzuki;T. Nakagawa;Y. Tada;Yukako Koura;A. Nishiyama;H. Okada;M. Uddin;A. Nabi;Y. Ishida;T. Inagami;T. Saruta
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作者：
A. Ichihara;M. Hayashi;Y. Kaneshiro;F. Suzuki;T. Nakagawa;Y. Tada;Yukako Koura;A. Nishiyama;H. Okada;M. Uddin;A. Nabi;Y. Ishida;T. Inagami;T. Saruta
我们发现，当一个位点特异性结合蛋白相互作用的“手柄”区域的前肾素前片段，前肾素分子经历了构象变化，其酶活性状态。这种非蛋白水解的激活被具有柄区结构的诱饵肽完全阻断，所述诱饵肽竞争性地结合到这样的结合蛋白。鉴于糖尿病患者血浆肾素原升高，我们研究了肾素原的非蛋白水解激活在糖尿病器官损伤中起重要作用的假设。链脲佐菌素诱导的糖尿病大鼠用柄区肽皮下给药治疗。在链脲佐菌素治疗后8周、16周和24周，测定代谢和肾脏组织学变化以及血浆和肾脏中的肾素-血管紧张素系统组分。糖尿病大鼠的肾脏含有增加的血管紧张素I和II，而没有任何变化，在肾素，血管紧张素转换酶，或血管紧张素原合成。然而，用柄区肽治疗降低了肾脏中Ang I和II的含量，并且完全抑制了糖尿病肾病的发展，而不影响高血糖。我们认为，非蛋白水解激活的原肾素可能是一个重要的机制，糖尿病肾病。其机制和引起非蛋白水解激活的物质可能成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.