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

我们发现，当一个位点特异的结合蛋白与前肾素前段的“手柄”区域相互作用时，原肾素分子经历了构象变化到其酶活性状态。这种非蛋白水解性激活完全被具有“手柄”区域结构的诱饵肽所阻断，这种诱饵肽竞争性地与这种结合蛋白结合。尽管糖尿病动物血浆前肾素水平较高，而肾素水平较低，提示循环RAS受到抑制，但血管紧张素II 1型受体拮抗剂在预防糖尿病器官损害的发生和发展方面具有良好的作用。我们检验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“柄”区肽进行治疗。…测定代谢和肾脏组织学改变以及血浆和肾脏中肾素-血管紧张素系统成分链脲佐菌素治疗后8周、16周和24周的患者更多。糖尿病大鼠肾脏血管紧张素I和血管紧张素II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。然而，“手柄”区肽的治疗降低了肾脏血管紧张素I和血管紧张素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能成为预防糖尿病器官损害的重要治疗靶点。此外，如果Prorenin及其受体的复合体也能够激活ERK1/ERK2通路，而不依赖于RAS的激活，那么受体和Prorenin之间的复合体形成的抑制剂不仅可以抑制RAS的激活，而且可以抑制RAS非依赖的ERK的激活，从而完全防止糖尿病器官损伤的发生。较少

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