title: Erythropoietin Synthesis in Renal Myofibroblasts Is Restored by Activation of Hypoxia Signaling.
abstract: Erythropoietin (Epo) is produced by renal Epo-producing cells (REPs) in a hypoxia-inducible manner. The conversion of REPs into myofibroblasts and coincident loss of Epo-producing ability are the major cause of renal fibrosis and anemia. However, the hypoxic response of these transformed myofibroblasts remains unclear. Here, we used complementary in vivo transgenic and live imaging approaches to better understand the importance of hypoxia signaling in Epo production. Live imaging of REPs in transgenic mice expressing green fluorescent protein from a modified Epo-gene locus revealed that healthy REPs tightly associated with endothelium by wrapping processes around capillaries. However, this association was hampered in states of renal injury-induced inflammation previously shown to correlate with the transition to myofibroblast-transformed renal Epo-producing cells (MF-REPs). Furthermore, activation of hypoxia-inducible factors (HIFs) by genetic inactivation of HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) selectively in Epo-producing cells reactivated Epo production in MF-REPs. Loss of PHD2 in REPs restored Epo-gene expression in injured kidneys but caused polycythemia. Notably, combined deletions of PHD1 and PHD3 prevented loss of Epo expression without provoking polycythemia. Mice with PHD-deficient REPs also showed resistance to LPS-induced Epo repression in kidneys, suggesting that augmented HIF signaling counterbalances inflammatory stimuli in regulation of Epo production. Thus, augmentation of HIF signaling may be an attractive therapeutic strategy for treating renal anemia by reactivating Epo synthesis in MF-REPs.
authors.affiliation: Department of Medical Biochemistry, Division of Interdisciplinary Medical Science, Division of Nephrology, Endocrinology, and Vascular Medicine, and.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Souma
authors.affiliation: Department of Medical Biochemistry, Division of Interdisciplinary Medical Science, Division of Nephrology, Endocrinology, and Vascular Medicine, and.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nezu
authors.affiliation: Department of Pharmacology, Kagawa University, Kagawa, Japan; and.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakano
authors.affiliation: Department of Medical Biochemistry, Division of Interdisciplinary Medical Science.
authors.forename: Shun
authors.initials: S
authors.lastname: Yamazaki
authors.affiliation: Department of Medical Biochemistry, Division of Interdisciplinary Medical Science.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Hirano
authors.affiliation: Department of Medical Biochemistry, Division of Interdisciplinary Medical Science.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sekine
authors.affiliation: Division of Molecular Medicine and Therapy, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors.forename: Takashi
authors.initials: T
authors.lastname: Dan
authors.affiliation: Department of Cell Biology, University of Connecticut Health Centre, Farmington, Connecticut.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Department of Cell Biology, University of Connecticut Health Centre, Farmington, Connecticut.
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Fong
authors.affiliation: Department of Pharmacology, Kagawa University, Kagawa, Japan; and.
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine, and.
authors.forename: Sadayoshi
authors.initials: S
authors.lastname: Ito
authors.affiliation: Division of Molecular Medicine and Therapy, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.affiliation: Department of Medical Biochemistry.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Division of Interdisciplinary Medical Science, sunorio@med.tohoku.ac.jp.
authors.forename: Norio
authors.initials: N
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D004921:Erythropoietin / Q000096:biosynthesis*; D007668:Kidney / Q000166:cytology*; D051379:Mice; D058628:Myofibroblasts / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D004921:Erythropoietin
keywords: Pathophysiology of Renal Disease and Progression; anemia; chronic kidney disease; erythropoietin; fibrosis; hypoxia