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Role of renin and the renin-producing cells for the functional and structural integrity of the kidney

肾素和肾素产生细胞对肾脏功能和结构完整性的作用

基本信息

批准号：
258497933
负责人：
Professor Dr. Vladimir Todorov
金额：
--
依托单位：
Lehrstuhl für Physiologie und Pathophysiologie
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/258497933?language=en
关键词：
Role renin producing cells functional

项目摘要

Renin is largely expressed throughout the renal arteries in embryonic life. In contrast, the expression of renin in adulthood is restricted to the afferent arterioles where it is produced mainly by the juxtaglomerular cells. The constitutive inactivation by genomic targeting as well as null mutations of the renin gene cause developmental malformations in the kidney. These are manifested by glomerulosclerosis, arterial thickening and tubular dysgenesis, and consequently result in deterioration of renal function and early death. On the other hand, the causal role of renin for the maintenance of normal kidney function in adulthood when nephrogenesis is accomplished is still largely unknown. In addition, it has been suggested that the renin-producing cells themselves independent of renin may also be essential for the morphological and functional integrity of the kidney. The current studies in this research area are essentially hampered by the lack of an appropriate experimental model.In the proposed project we will address this issue by using transgenic mouse model for selective and inducible targeting of the renin-producing cells. We have already generated a mouse line (mRen-rtTAm2) expressing tetracycline transactivator under the control of the complete regulatory sequences of the renin gene. The mRen-rtTAm2 transgenic mice crossed with a tetracycline-inducible cre-recombinase expressing strain (LC1 mice) allow us to modulate the renin gene expression or to selectively ablate the renin-producing cells after the kidney development is completely finished.Using this transgenic model we will first study whether the inducible genomic inactivation of the renin gene leads to changes in the kidney phenotype. For this purpose we have already generated a transgenic mouse line with a floxed renin allele.In a second approach we will characterize the renal excretory function and morphology of mice in which the renin-producing cells are selectively destroyed. To this end, we will use animals with inducible expression of diphtheria toxin A chain in renin cells. Furthermore, we will examine the role of the orphan nuclear receptor COUP-TFII in renin cells. COUP-TFII regulates the renin gene expression by modulating the cAMP signaling, which in turn is the master switch of the renin production. Therefore we generated mice with inducible deficiency of COUP-TFII.We expect from these experiments to provide comprehensive insight into the renin-dependent and independent role of the renin-producing cells for the physiological integrity of the kidney beyond nephrogenesis. In a perspective our data could accelerate the development of novel therapeutic strategies based on the modulation of the renin-angiotensin-system, the renin production and/or the number of the renin-producing cells to beneficially influence the mechanisms of kidney repair during chronic kidney disease.

在胚胎生命中，肾素在整个肾动脉中大量表达。相反，成年期的肾素表达仅限于传入小动脉，主要由肾小球细胞产生。基因组靶向的组成性失活以及肾素基因的无效突变导致肾脏发育畸形。这些表现为肾小球硬化、动脉增厚和肾小管发育不全，并因此导致肾功能恶化和早期死亡。另一方面，成人期肾形成完成后，肾素对维持正常肾功能的因果作用仍不清楚。此外，已经提出，不依赖于肾素的产生肾素的细胞本身也可能对肾脏的形态和功能完整性至关重要。目前这一领域的研究主要是由于缺乏合适的实验模型而受到阻碍，本研究拟利用转基因小鼠模型来选择性和诱导性靶向肾素产生细胞，以解决这一问题。我们已经产生了一个小鼠系（mRen-rtTAm 2）表达四环素反式激活蛋白的控制下的完整的调节序列的肾素基因。mRen-rtTAm 2转基因小鼠与四环素诱导的cre重组酶表达株（LC 1小鼠）杂交，使我们能够在肾脏发育完全后调节肾素基因表达或选择性地清除产生肾素的细胞，利用这种转基因模型，我们将首先研究诱导的肾素基因组失活是否导致肾脏表型的改变。为此目的，我们已经产生了一个转基因小鼠系与floxed肾素等位基因。在第二种方法中，我们将描述小鼠的肾脏排泄功能和形态学中的肾素产生细胞被选择性破坏。为此，我们将使用在肾素细胞中具有白喉毒素A链诱导表达的动物。此外，我们将研究孤儿核受体COUP-TFII在肾素细胞中的作用。COUP-TFII通过调节cAMP信号来调节肾素基因表达，cAMP信号反过来又是肾素产生的主开关。因此，我们产生的小鼠与诱导缺陷的COUP-TFII。我们期望从这些实验中提供全面的洞察到肾素依赖性和独立的作用的肾素生产细胞的生理完整性的肾脏超越肾发生。从某种角度来看，我们的数据可以加速基于调节肾素-血管紧张素系统、肾素产生和/或产生肾素的细胞数量的新治疗策略的开发，以有益地影响慢性肾脏疾病期间的肾脏修复机制。