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

肾素（原）受体的肾素依赖性和独立功能

• 批准号: 266599085
• 负责人: Professor Dr. Ulrich Wenzel
• 金额: --
• 依托单位: III. Medizinische Klinik und Poliklinik (Nephrologie, Rheumatologie - Nierentransplantation - Sektion Endokrinologie/Diabetologie)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/266599085?language=en
• 关键词: Renin; dependent; independent; functions; pro

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.

在体外，肾素和原肾素与（原）肾素受体的结合增加了它们的酶活性并上调了促纤维化基因的表达。这些是所谓的（原）肾素受体的肾素依赖性功能。非肾素依赖性功能与其作为V-ATP酶的辅助亚基和参与信号体有关。由于V-ATP酶对于细胞存活是必不可少的，这使得敲除实验中PRR的分析复杂化。为了确定增加的（原）肾素受体表达是否会导致器官损伤，我们产生了一个转基因小鼠有条件地过表达小鼠（原）肾素受体。这种转基因小鼠没有基础表型。对于本申请，我们的目的是检查受体的过表达在肾素血管紧张素系统的激活期间是否是致病性的，或者是否调节慢性肾病、糖尿病或先兆子痫中的疾病严重性。可以从35 kDa大小的全长（原）肾素受体切割28 kDa大小的细胞外片段。这种可溶性受体片段被分泌并可在组织和血浆中发现。然而，可溶性受体的病理生理功能仍然是未知的。为了进一步研究可溶性（原）肾素受体在体内的功能，我们正在产生一个转基因小鼠，过表达可溶性（原）肾素受体。在体外，可溶性受体能够拯救全长受体蛋白的敲除。通过将过表达可溶性受体的转基因小鼠与（原）肾素受体敲除小鼠杂交，我们将能够检查可溶性受体是否也可以在体内挽救全长受体的敲除。此外，我们将研究可溶性（原）肾素受体是否可以淬灭体内的肾素和原肾素，并发挥对血压和肾损伤的保护作用。本项目将增加我们对（原）肾素受体及其可溶性部分的认识。可溶性（原）肾素受体可能是动脉高血压和肾脏疾病治疗干预的新靶点。

项目成果

The complement receptor C5aR1 contributes to renal damage but protects the heart in angiotensin II-induced hypertension.

• DOI: 10.1152/ajprenal.00040.2016
• 发表时间: 2016-06
• 期刊: American journal of physiology. Renal physiology
• 作者: S. Weiss;A. Rosendahl;Daniel Czesla;C. Meyer-Schwesinger;R. Stahl;H. Ehmke;C. Kurts;P. Zipfel;J. Köhl;U. Wenzel

ATP6AP2 over-expression causes morphological alterations in the hippocampus and in hippocampus-related behaviour

• DOI: 10.1007/s00429-018-1633-1
• 发表时间: 2018-06-01
• 期刊: BRAIN STRUCTURE & FUNCTION
• 影响因子: 3.1
• 作者: Bracke, A.;Schaefer, S.;Halbach, O. Von Bohlen Und
• 通讯作者: Halbach, O. Von Bohlen Und