title: Distinct subpopulations of FOXD1 stroma-derived cells regulate renal erythropoietin.
abstract: Renal peritubular interstitial fibroblast-like cells are critical for adult erythropoiesis, as they are the main source of erythropoietin (EPO). Hypoxia-inducible factor 2 (HIF-2) controls EPO synthesis in the kidney and liver and is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2, and PHD3, which function as cellular oxygen sensors. Renal interstitial cells with EPO-producing capacity are poorly characterized, and the role of the PHD/HIF-2 axis in renal EPO-producing cell (REPC) plasticity is unclear. Here we targeted the PHD/HIF-2/EPO axis in FOXD1 stroma-derived renal interstitial cells and examined the role of individual PHDs in REPC pool size regulation and renal EPO output. Renal interstitial cells with EPO-producing capacity were entirely derived from FOXD1-expressing stroma, and Phd2 inactivation alone induced renal Epo in a limited number of renal interstitial cells. EPO induction was submaximal, as hypoxia or pharmacologic PHD inhibition further increased the REPC fraction among Phd2-/- renal interstitial cells. Moreover, Phd1 and Phd3 were differentially expressed in renal interstitium, and heterozygous deficiency for Phd1 and Phd3 increased REPC numbers in Phd2-/- mice. We propose that FOXD1 lineage renal interstitial cells consist of distinct subpopulations that differ in their responsiveness to Phd2 inactivation and thus regulation of HIF-2 activity and EPO production under hypoxia or conditions of pharmacologic or genetic PHD inactivation.
authors.forename: Hanako
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Qingdu
authors.initials: Q
authors.lastname: Liu
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Binns
authors.forename: Andres A
authors.initials: AA
authors.lastname: Urrutia
authors.forename: Olena
authors.initials: O
authors.lastname: Davidoff
authors.forename: Pinelopi P
authors.initials: PP
authors.lastname: Kapitsinou
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Pfaff
authors.forename: Hannes
authors.initials: H
authors.lastname: Olauson
authors.forename: Annika
authors.initials: A
authors.lastname: Wernerson
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Fong
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Gross
authors.forename: Volker H
authors.initials: VH
authors.lastname: Haase
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D004921:Erythropoietin / Q000096:biosynthesis* / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D051858:Forkhead Transcription Factors; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D011393:Procollagen-Proline Dioxygenase; C489562:Foxd1 protein, mouse; C522721:PHD1 protein, mouse; C522722:PHD3 protein, mouse; C490189:Egln1 protein, mouse