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 systemwith renin-1d promoter-driven Cre expression. Vhl-/-RENmice were viable and had normal BP. Deletion of Vhl resulted in constitutive accumulation of HIF-2α in afferent arterioles and glomerular cells andHIF-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 combinedwith anACE 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. Copyright © 2013 by the American Society of Nephrology.