Renin dependent and independent functions of the (pro)renin receptor

肾素和前肾素与(PRO)肾素受体的结合增加了它们的酶活性，并在体外上调了促纤维化基因的表达。这些都是所谓的肾素依赖功能的(原)肾素受体。肾素非依赖性功能与其作为V-ATPase辅助亚单位的功能和参与信号小体有关。由于V-ATPase对于细胞生存是必不可少的，这使得在基因敲除实验中分析PRR变得复杂。为了确定(PRO)肾素受体表达增加是否会导致器官损伤，我们培育了一只有条件地过度表达小鼠(PRO)肾素受体的转基因小鼠。这只转基因小鼠没有基本的表型。通过目前的应用，我们的目的是检查该受体的过度表达是否在肾素血管紧张素系统激活期间是致病的，或者调节慢性肾脏疾病、糖尿病或先兆子痫的疾病严重程度。一个28 kDa的胞外片段可以从35 kDa的全长(Pro)肾素受体上切割出来。这种可溶的受体片段被分泌出来，在组织和血浆中都可以找到。然而，可溶性受体的病理生理功能仍不清楚。为了进一步研究可溶性(PRO)肾素受体在体内的功能，我们正在培育一种过表达可溶性(PRO)肾素受体的转基因小鼠。在体外，可溶性受体能够挽救全长受体蛋白的敲除。通过将高表达可溶性受体的转基因小鼠与(PRO)肾素受体敲除小鼠杂交，我们将能够检验可溶性受体是否也能在体内挽救全长受体的敲除。此外，我们还将研究可溶性(PRO)肾素受体是否能够在体内猝灭肾素和前肾素，并对血压和肾脏损伤起到保护作用。这个项目将增加我们对(原)肾素受体及其可溶性部分的了解。可溶性(PRO)肾素受体可能成为动脉高血压和肾脏疾病治疗干预的新靶点。

Binding of renin and prorenin to the (pro)renin receptor increases their enzymatic activity and up-regulates the expression of pro-fibrotic genes in vitro. These are the so called renin-dependent functions of the (pro)renin receptor. The renin-independent functions are related to its function as an accessory subunit of the V-ATPase and its participation in the signalosome. Since the V-ATPase is essential for cell survival, this complicates the analysis of the PRR in knockout experiments. To establish whether increased (pro)renin receptor expression could cause organ damage, we generated a transgenic mouse which conditionally overexpresses the mouse (pro)renin receptor. This transgenic mouse has no basal phenotype. With the present application we aim to examine whether overexpression of the receptor is pathogenic during activation of the renin angiotensin system or modulates disease severity in chronic kidney disease, diabetes mellitus or preeclampsia. A 28 kDa sized extracellular fragment can be cleaved from the 35 kDa sized full-length (pro)renin receptor. This soluble receptor fragment gets secreted and can be found in tissue and plasma. However, the pathophysiologic function of the soluble receptor is still unknown. To further examine the in vivo function of the soluble (pro)renin receptor, we are generating a transgenic mouse that overexpresses the soluble (pro)renin receptor. In vitro the soluble receptor is capable to rescue the knockout of the full-length receptor protein. By crossing the transgenic mouse overexpressing the soluble receptor with the (pro)renin receptor knockout mouse we will be able to examine whether the soluble receptor can also rescue the knockout of the full-length receptor in vivo. In addition, we will examine whether the soluble (pro)renin receptor can quench renin and prorenin in vivo and exerts protective effects on blood pressure and renal injury. This project will increase our knowledge about the (pro)renin receptor and its soluble part. The soluble (pro)renin receptor could represent a new target for therapeutic interventions in arterial hypertension and kidney disease.