Prolyl‐4‐hydroxylases 2 and 3 control erythropoietin production in renin‐expressing cells of mouse kidneys

Activation of the hypoxia‐signalling pathway induced by deletion of the ubiquitin‐ligase von Hippel–Lindau protein causes an endocrine shift of renin‐producing cells to erythropoietin (EPO)‐expressing cells. However, the underlying mechanisms have not yet been investigated. Since oxygen‐regulated stability of hypoxia‐inducible transcription factors relevant for EPO expression is dependent on the activity of prolyl‐4‐hydroxylases (PHD) 2 and 3, this study aimed to determine the relevance of different PHD isoforms for the EPO expression in renin‐producing cells in vivo . For this purpose, mice with inducible renin cell‐specific deletions of different PHD isoforms were analysed. Our study shows that there are two subgroups of renal renin‐expressing cells, juxtaglomerular renin + cells and platelet‐derived growth factor receptor‐β + interstitial renin + cells. These interstitial renin + cells belong to the cell pool of native EPO‐producing cells and are able to express EPO and renin in parallel. In contrast, co‐deletion of PHD2 and PHD3, but not PHD2 deletion alone, induces EPO expression in juxtaglomerular and hyperplastic renin + cells and downregulates renin expression. A strong basal PHD3 expression in juxtaglomerular renin + cells seems to prevent the hypoxia‐inducible transcription factor‐2‐dependent phenotype shift into EPO cells. In summary, PHDs seem important for the stabilization of the juxtaglomerular renin cell phenotype. Moreover, these findings reveal tubulointerstitial cells as a novel site of renal renin expression and suggest a high endocrine plasticity of these cells. Our data concerning the distinct expression patterns and functions of PHD2 and PHD3 provide new insights into the regulation of renin‐producing cells and highlight the need for selective PHD inhibitors. Key points Renal renin‐expressing cells can be clearly distinguished into two subgroups, the typical juxtaglomerular renin‐producing cells and interstitial renin + cells. Interstitial renin + cells belong to the cell pool of native erythropoietin (EPO)‐producing cells, show a fast EPO response to acute hypoxia‐inducible factor‐2 (HIF‐2) stabilization and are able to express EPO and renin in parallel. Only co‐deletion of the prolyl‐4‐hydroxylases (PHD) 2 and 3, but not PHD2 deletion alone, induces EPO expression in juxtaglomerular renin + cells. Chronic HIF‐2 stabilization in juxtaglomerular renin‐expressing cells leads to their phenotypic shift into EPO‐producing cells. A strong basal PHD3 expression in juxtaglomerular renin + cells seems to prevent a HIF‐2‐dependent phenotype shift into EPO cells suggesting PHD3 fulfils a stabilizer function for the juxtaglomerular renin cell phenotype.