title: Deletion of von Hippel-Lindau protein converts renin-producing cells into erythropoietin-producing cells.
abstract: States of low perfusion pressure of the kidney associate with hyperplasia or expansion of renin-producing cells, but it is unknown whether hypoxia-triggered genes contribute to these changes. Here, we stabilized hypoxia-inducible transcription factors (HIFs) in mice by conditionally deleting their negative regulator, Vhl, using the Cre/loxP system with renin-1d promoter-driven Cre expression. Vhl (−/−(REN)) mice were viable and had normal BP. Deletion of Vhl resulted in constitutive accumulation of HIF-2α in afferent arterioles and glomerular cells and HIF-1α in collecting duct cells of the adult kidney. The preglomerular vascular tree developed normally, but far fewer renin-expressing cells were present, with more than 70% of glomeruli not containing renin cells at the typical juxtaglomerular position. Moreover, these mice had an attenuated expansion of renin-producing cells in response to a low-salt diet combined with an ACE inhibitor. However, renin-producing cells of Vhl (−/−(REN)) mice expressed the erythropoietin gene, and they were markedly polycythemic. Taken together, these results suggest that hypoxia-inducible genes, regulated by VHL, are essential for normal development and physiologic adaptation of renin-producing cells. In addition, deletion of Vhl shifts the phenotype of juxtaglomerular cells from a renin- to erythropoietin-secreting cell type, presumably in response to HIF-2 accumulation.
authors: Institute of Physiology, University of Regensburg, D-93053 Regensburg, Germany. birguel.kurt@vkl.uni-regensburg.de
authors: Birguel
authors: B
authors: Kurt
authors: Alexander
authors: A
authors: Paliege
authors: Carsten
authors: C
authors: Willam
authors: Ilona
authors: I
authors: Schwarzensteiner
authors: Kathrin
authors: K
authors: Schucht
authors: Hanna
authors: H
authors: Neymeyer
authors: Maria Luisa S
authors: ML
authors: Sequeira-Lopez
authors: Sebastian
authors: S
authors: Bachmann
authors: R Ariel
authors: RA
authors: Gomez
authors: Kai-Uwe
authors: KU
authors: Eckardt
authors: Armin
authors: A
authors: Kurtz
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D004921:Erythropoietin / Q000096:biosynthesis* / Q000235:genetics; D018390:Gene Targeting; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007606:Juxtaglomerular Apparatus / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012083:Renin / Q000096:biosynthesis* / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D012083:Renin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C494469:VHL protein, mouse
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