Relevance of von Hippel-Lindau protein for differentiation of renal renin expressing cells

随着促红细胞生成素(EPO)和肾素(作为肾素-血管紧张素-醛固酮系统的激活剂)的产生，肾脏完成了两项中枢内分泌功能，决定了血容量、氧运输、血管阻力和血压。EPO细胞和肾素产生细胞表现出不同的区域定位和不同的超微结构，它们感知不同的生理相关参数，如红细胞压积或肾脏灌注压。我们最近的数据表明，产生EPO和肾素的细胞比之前认为的更接近。这两种细胞都是从FoxD1阳性基质祖细胞库发展而来的，都表现出周细胞的特征，最令人印象深刻的是，当von Hippel Lindau蛋白功能丧失时，肾素产生细胞以HIF2依赖的方式转化为EPO产生细胞。基于这些发现，我们现在想要研究体内细胞转化这一惊人现象的更多细节。首先，我们将确定肾素和EPO的表达是否相互排斥，并与特定的细胞分化状态有关。在这方面，我们还将研究在特定的病理生理条件下，肾素产生细胞是否也能产生EPO。由于低氧信号通路的活性主要由细胞氧合张力和特定的脯氨酸羟基酶(PHD)活性决定，因此我们将测定和比较天然肾素生产细胞和EPO生产细胞的PHD功能亚型模式。关于肾素的化生转化为产生EPO的细胞，我们想确定这个过程是否严格地由HIF2触发。在这方面，我们还将确定这一进程是否可逆。最后，我们将研究肾素转化为EPO产生细胞过程中基因表达谱的变化，以及在此背景下特征基因的启动子是否发生改变，如EPO、RGS4、肾素、Akr1b7。我们期待关于肾脏血管周围细胞可塑性的新的基础信息。此外，我们的研究可能为HIF2作为分化因子的功能提供新的信息。

With the production of erythropoietin (EPO) and of renin (as the activator of the renin-angiotensin-aldosterone system) the kidneys fulfil two central endocrine functions which determine blood volume, oxygen transport, vascular resistance and blood pressure. The EPO- and the renin producing cells show a different regional localization, different ultrastructure and they perceive different physiologically relevant parameters such as hematocrit or the renal perfusion pressure. Our recent data now suggest that EPO- and renin producing cells are more closely rated than previously thought. Both cell types develop from the FoxD1 positive stroma progenitor cell pool, both show characteristics of pericytes and most impressively renin producing cells transform into EPO producing cells upon loss of function of the von Hippel Lindau protein in a HIF2 dependent manner. Based upon these findings we now want to investigate more details of this striking phenomenon of cellular transformation in vivo. First we will determine if the expression of renin and of EPO is mutually exclusive and is linked to a specific cellular differentiation state. In this context we will also examine if under certain pathophysiological conditions renin producing cells are capable to produce also EPO. As the activity of the hypoxia signaling pathway is essentially determined by the cellular oxgyen tension and the activity of specific prolylhydroxylases (PHD) we will determine and compare the functional PHD isoform pattern of native renin producing and of EPO producing cells. In regard of the metaplastic transformation of renin into EPO producing cells we want to determine if this process is strictly triggered by HIF2. In this context we will also determine if this process is reversible. Finally we will investigate the changes of the gene expression profiles occurring during the switch of renin into EPO producing cells and if the promotors of characteristic genes in this context such as for EPO, RGS4, renin, Akr1b7 undergo modifications.We expect new fundamental informations about the plasticity of perivascular cells of the kidneys. Moreover, our investigations could provide new informations about the function of HIF2 as a differentiation factor.