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

Autor: Broeker KAE; Institute of Physiology, University of Regensburg, Regensburg, Germany., Fuchs MAA; Institute of Physiology, University of Regensburg, Regensburg, Germany., Schrankl J; Institute of Physiology, University of Regensburg, Regensburg, Germany., Lehrmann C; Institute of Physiology II, University of Regensburg, Regensburg, Germany., Schley G; Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany., Todorov VT; Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany., Hugo C; Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany., Wagner C; Institute of Physiology, University of Regensburg, Regensburg, Germany., Kurtz A; Institute of Physiology, University of Regensburg, Regensburg, Germany.
Jazyk: angličtina
Zdroj: The Journal of physiology [J Physiol] 2022 Feb; Vol. 600 (3), pp. 671-694. Date of Electronic Publication: 2021 Dec 27.
DOI: 10.1113/JP282615
Abstrakt: 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.
(© 2021 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)
Databáze: MEDLINE
Externí odkaz: