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

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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.