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Effects of pressure-dependent regulation of prorenin synthesis and secretion on progression of diabetic nephropathy

压力依赖性肾素原合成和分泌调节对糖尿病肾病进展的影响

基本信息

批准号：
14571073
负责人：
ICHIHARA Atsuhiro
金额：
$ 1.79万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

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 non-proteolytic activation is completely blocked by a decoy peptide with the "handle" region structure, which competitively binds to such a binding protein. Even though diabetic animals have high plasma prorenin levels and low plasma renin levels, suggesting a suppressed circulating RAS, angiotensin II type 1 receptor blockers have a beneficial effect in preventing the development and progression of diabetic organ damage. We examined the hypotheses that the non-proteolytic 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-angiotensin system components in the plasma and kidneys were determined … More at 8,16, and 24 weeks following streptozotocin treatment. Kidneys of diabetic rats contained increased angiotensin I and II without any changes in renin, angiotensin converting enzyme, or angiotensinogen synthesis. However, treatment with the "handle" region peptide decreased the renal content of angiotensin I and II and completely inhibited the development of diabetic nephropathy without affecting hyperglycemia. We propose that the non-proteolytic activation of prorenin may be a significant mechanism of diabetic nephropathy. The mechanism and substances causing non-proteolytic activation of prorenin may serve as important therapeutic target for the prevention of diabetic organ damage. Also, if the complex of prorenin and its receptor is also able to activate the ERK1/ERK2 pathways independently of the RAS activation as proposed by Nguyen et al., it is possible that an inhibitor of complex formation between the receptor and prorenin can completely prevent the development of diabetic organ damages through the inhibition of not only the RAS activation but also the RAS-independent ERK activation. Less

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。这种非蛋白水解活化被具有“柄”区结构的诱饵肽完全阻断，所述诱饵肽竞争性结合到这样的结合蛋白。尽管糖尿病动物具有高血浆原肾素水平和低血浆肾素水平，表明循环RAS受抑制，但血管紧张素II 1型受体阻断剂在预防糖尿病器官损伤的发生和进展方面具有有益作用。我们研究了非蛋白水解激活的前肾素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皮下施用“柄”区域肽治疗。测定代谢和肾脏组织学变化以及血浆和肾脏中的肾素-血管紧张素系统成分 ...更多信息在链脲佐菌素治疗后8、16和24周。糖尿病大鼠肾脏血管紧张素I和II含量增加，而肾素、血管紧张素转换酶或血管紧张素原合成无任何变化。然而，用“柄”区肽治疗降低了肾血管紧张素I和II的含量，并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。其非蛋白水解激活的机制和物质可能成为预防糖尿病器官损害的重要治疗靶点。此外，如果如Nguyen等人所提出的那样，原肾素及其受体的复合物也能够独立于RAS激活而激活ERK 1/ERK 2途径，受体和前肾素之间复合物形成的抑制剂可能通过不仅抑制RAS活化而且抑制RAS非依赖性ERK活化而完全防止糖尿病器官损伤的发展。少