structure of prorenin molecule

2005年，我们利用链脲佐菌素诱导的糖尿病血管紧张素II 1型受体缺陷小鼠，提供了证据，证明人原肾素与人（原）肾素受体结合引起的血管紧张素II非依赖性途径显著促进糖尿病肾病的发生和发展。2006年，我们使用培养的人血管平滑肌细胞，观察到人（原）肾素受体定位于细胞质中靠近细胞核的位置，并通过原肾素的负载将其转座到细胞核中。此外，大鼠原肾素能够与人（原）肾素受体结合，从而刺激受体依赖性细胞内信号，但不通过与人（原）肾素受体结合而激活。在人血管平滑肌细胞中，人原肾素刺激MAP激酶途径，通过与人（原）肾素受体结合，独立于血管紧张素II，导致细胞增殖。在2007年，我们开发了人（原）肾素受体转基因大鼠，其没有增强的组织肾素-血管紧张素系统，因为大鼠原肾素不能通过与人（原）肾素受体结合而被激活。然而，人（原）肾素受体转基因大鼠有一个增强的（原）肾素受体依赖的细胞内信号通路，和缓慢进行性肾病，即肾小球硬化症与蛋白尿的发展在转基因大鼠。发生在转基因大鼠中的肾病的发展是由受体依赖性MAP激酶途径引起的，并且与血压或肾脏血管紧张素II水平无关。因此，人（原）肾素受体转基因大鼠被认为是有用的研究人（原）肾素受体的信号在体内。

In 2005, using streptozotocin-induced diabetic angiotensin-II-type-1-receptor-deficient-mice, we provided the evidence that angiotensin II-independent pathway caused by binding of human prorenin to human (pro)renin receptor significantly contributes to the development and progression of diabetic nephropathy. In 2006, using human cultured vascular smooth muscle cells, we observed the localization of human (pro)renin receptor in the cytosol close to nucleus and its transposition into the nucleus by the load of prorenin. In addition, rat prorenin was capable of binding to human (pro)renin receptor and thus stimulating the receptor-dependent intracellular signals but was not activated by binding to human (pro)renin receptor. In human vascular smooth muscle cells, human prorenin stimulated the MAP kinase pathways, leading to cell proliferation, through binding to human (pro)renin receptor independently of angiotensin II. In 2007, we developed human-(pro)renin-receptor-transgenic rats which have no enhanced tissue renin-angiotensin system because rat prorenin is incapable of being activated by binding to human (pro)renin receptor. However, the human-(pro)renin-receptor-transgenic rats had an enhanced (pro)renin receptor-dependent intracellular signaling pathways, and slowly progressive nephropathy, that is glomerulosclerosis with proteinuria developed in the transgenic rats. The development of nephropathy occurred in the transgenic rats was caused by the receptor-dependent MAP kinase pathways and was independent of blood pressure or renal angiotensin II levels. Thus, the human-(pro)renin-receptor-transgenic rats was thought to be useful for studying the signals of human(pro)renin receptor in vivo.