Contribution of nonproteolytically activated prorenin in glomeruli to hypertensive renal damage
Contribution of nonproteolytically activated prorenin in glomeruli to hypertensive renal damage
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DOI：
10.1681/asn.2005121278
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发表时间：
2006-09-01
影响因子：
13.6
通讯作者：
Inagami, Tadashi
中科院分区：
文献类型：
--
作者：
Ichihara, Atsuhiro;Kaneshiro, Yuki;Inagami, Tadashi
前肾素通过前肾素受体与前肾素前片段的五聚体“柄区”（HR）结合而被激活，而无需蛋白水解。据推测，这种激活发生在高血压大鼠的肾脏，并导致组织肾素-血管紧张素系统（RAS）激活和终末器官损伤。由于HR与其结合蛋白的结合使得其特异性抗体可接近相邻的四聚体“门区”（GR），因此进行GR的免疫组织化学以检验该假设。还专门设计了方法来抑制非蛋白水解激活的十肽对应的HR作为诱饵。GR的免疫组织化学表明，大多数非蛋白水解激活的前肾素存在于易中风自发性高血压大鼠肾脏的足细胞中，其中发生了肾组织RAS激活、蛋白尿和肾小球硬化。连续皮下注射HR诱饵肽完全抑制组织原肾素的非蛋白水解激活和组织RAS的激活，而不影响循环RAS或动脉压，并显着减弱蛋白尿和肾小球硬化症的发展和进展。这些研究清楚地表明，非蛋白水解激活的原肾素在肾小球是关键参与肾组织RAS激活，导致肾损害的高血压动物。
Prorenin is activated without proteolysis by binding of prorenin receptor to the pentameric "handle region" (HR) of prorenin prosegment. It was hypothesized that such activation occurs in the kidneys of hypertensive rats and causes tissue renin-angiotensin system (RAS) activation and end-organ damage. Because the HR's binding to its binding protein made the adjacent tetrameric "gate region" (GR) accessible to its specific antibody, immunohistochemistry of the GR was performed to test the hypothesis. Methods also were devised specifically to inhibit the nonproteolytic activation by the decapeptide corresponding to the HR as a decoy. Immunohistochemistry of the GR demonstrated that the majority of nonproteolytically activated prorenin is present in podocytes of the kidneys from stroke-prone spontaneously hypertensive rats, in which activation of renal tissue RAS, proteinuria, and glomerulosclerosis occurred. Continuous subcutaneous administration of the HR decoy peptide completely inhibited both nonproteolytic activation of tissue prorenin and activation of tissue RAS without affecting circulating RAS or arterial pressure and significantly attenuated the development and progression of proteinuria and glomerulosclerosis. These studies clearly demonstrated that nonproteolytic activation of prorenin in glomeruli is critically involved in renal tissue RAS activation, leading to renal damage in hypertensive animals.