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

肾素在胚胎时期在整个肾动脉中大量表达。相反，成人肾素的表达仅限于传入小动脉，主要由肾小球旁细胞产生。基因组靶向的组成性失活以及肾素基因的零突变导致肾脏发育畸形。表现为肾小球硬化、动脉增厚和肾小管发育不良，从而导致肾功能恶化和早期死亡。另一方面，肾素在成人肾形成时维持正常肾功能的因果作用仍然很大程度上是未知的。此外，有研究表明，独立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。目前在这一研究领域的研究基本上受到缺乏适当的实验模型的阻碍。在本项目中，我们将利用转基因小鼠模型对肾素产生细胞进行选择性和诱导靶向。我们已经在肾素基因的完整调控序列的控制下产生了表达四环素反激活子的小鼠系（mRen-rtTAm2）。mRen-rtTAm2转基因小鼠与四环素诱导的表达肾素重组酶的菌株（LC1小鼠）杂交，使我们能够调节肾素基因表达或在肾脏发育完全完成后选择性地切除产生肾素的细胞。利用这种转基因模型，我们将首先研究肾素基因的可诱导基因组失活是否会导致肾脏表型的变化。为此目的，我们已经产生了一种带有柔粒肾素等位基因的转基因小鼠系。在第二种方法中，我们将描述肾素产生细胞被选择性破坏的小鼠的肾脏排泄功能和形态。为此，我们将使用在肾素细胞中诱导表达白喉毒素A链的动物。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的表达，而cAMP又是肾素产生的总开关。因此，我们制造了诱导性COUP-TFII缺乏的小鼠。我们期望从这些实验中全面了解肾素产生细胞对肾脏生理完整性的依赖和独立作用。从某种角度来看，我们的数据可以加速基于肾素-血管紧张素系统、肾素产生和/或产生肾素的细胞数量的调节的新治疗策略的发展，从而有益地影响慢性肾脏疾病期间肾脏修复的机制。

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.