Nonproteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension
Nonproteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension
复制标题
DOI：
10.1161/01.hyp.0000215838.48170.0b
复制
发表时间：
2006-05-01
期刊：
影响因子：
8.3
通讯作者：
Hayashi, M
中科院分区：
文献类型：
--
作者：
Ichihara, A;Kaneshiro, Y;Hayashi, M
与通过切割 N 端 43 个残基肽来蛋白水解激活无活性的肾素原相反，我们发现肾素原通过将肾素原受体与五聚体“手柄区域”(ILLKK15P)-L-11P 结合而无需蛋白水解即可激活。我们假设这种激活发生在高血压大鼠中，并导致心脏肾素-血管紧张素系统（RAS）激活和终末器官损伤。为了检验这一假设，我们设计了通过跨越五聚手柄区肽的十肽作为诱饵来特异性抑制非蛋白水解激活的方法。在饲喂高盐饮食的易发生中风的自发性高血压大鼠（SHRsp）中，动脉压在8周龄时开始显着升高，心脏肾素受体mRNA水平显着增加，并且在12周龄时出现心脏纤维化。通过使用针对肾素分子活性位点的抗体进行免疫组织化学分析，我们证明了心脏中肾素原的蛋白水解或非蛋白水解活性增加，但在 SHRsp 的血浆中却没有增加。连续皮下施用手柄区肽完全抑制了肾素分子活性位点抗体染色的增加，表明SHRsp心脏中肾素原的非蛋白水解活性增加，但蛋白水解活性没有增加。施用手柄区肽还可使组织 RAS 失活，而不影响循环 RAS 或动脉压，并显着减弱心脏纤维化的发生和进展。这些结果清楚地证明了非蛋白水解激活的组织肾素原在导致心脏纤维化的组织 RAS 激活中的重要作用，以及对长期输注手柄区肽所产生的心脏损伤的显着抑制。
In contrast to proteolytic activation of inactive prorenin by cleavage of the N-terminal 43 residue peptide, we found that prorenin is activated without proteolysis by binding of the prorenin receptor to the pentameric "handle region" (ILLKK15P)-L-11P. We hypothesized that such activation occurs in hypertensive rats and causes cardiac renin-angiotensin system (RAS) activation and end-organ damage. To test this hypothesis, we devised methods of specifically inhibiting nonproteolytic activation by decapeptide spanning the pentameric handle region peptide as a decoy. In stroke-prone spontaneously hypertensive rats (SHRsp) fed a high-salt diet, arterial pressure started to rise significantly with a marked increase in the cardiac prorenin receptor mRNA level at 8 weeks of age, and cardiac fibrosis had developed by 12 weeks of age. By immunohistochemistry using antibodies to the active site of the renin molecule, we demonstrated increased proteolytic or nonproteolytic activation of prorenin in the heart but not in plasma of SHRsp. Continuous subcutaneous administration of the handle region peptide completely inhibited the increased staining by antibodies to the active site of the renin molecule, indicating the increased nonproteolytic but not proteolytic activation of prorenin in the heart of SHRsp. Administration of the handle region peptide also inactivated tissue RAS without affecting circulating RAS or arterial pressure and significantly attenuated the development and progression of cardiac fibrosis. These results clearly demonstrate the significant role of nonproteolytically activated tissue prorenin in tissue RAS activation leading to cardiac fibrosis and significant inhibition of the cardiac damage produced by chronic infusion of the handle region peptide.