title: Renal Anemia Model Mouse Established by Transgenic Rescue with an Erythropoietin Gene Lacking Kidney-Specific Regulatory Elements.
abstract: The erythropoietin (Epo) gene is under tissue-specific inducible regulation. Because the kidney is the primary EPO-producing tissue in adults, impaired EPO production in chronic kidney disorders results in serious renal anemia. The Epo gene contains a liver-specific enhancer in the 3' region, but the kidney-specific enhancer for gene expression in renal EPO-producing (REP) cells remains elusive. Here, we examined a conserved upstream element for renal Epo regulation (CURE) region that spans 17.4 kb to 3.6 kb upstream of the Epo gene and harbors several phylogenetically conserved elements. We prepared various Epo gene-reporter constructs utilizing a bacterial artificial chromosome and generated a number of transgenic-mouse lines. We observed that deletion of the CURE region (δCURE) abrogated Epo gene expression in REP cells. Although transgenic expression of the δCURE construct rescued Epo-deficient mice from embryonic lethality, the rescued mice had severe EPO-dependent anemia. These mouse lines serve as an elaborate model for the search for erythroid stimulatory activity and are referred to as AnRED (anemic model with renal EPO deficiency) mice. We also dissected the CURE region by exploiting a minigene harboring four phylogenetically conserved elements in reporter transgenic-mouse analyses. Our analyses revealed that Epo gene regulation in REP cells is a complex process that utilizes multiple regulatory influences.
authors.affiliation: Department of Molecular Hematology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Hirano
authors.affiliation: Division of Oxygen Biology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Yamazaki
authors.affiliation: Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sekine
authors.affiliation: Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Minegishi
authors.affiliation: Department of Molecular Hematology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan rshimizu@med.tohoku.ac.jp masiyamamoto@med.tohoku.ac.jp.|Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Shimizu
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan rshimizu@med.tohoku.ac.jp masiyamamoto@med.tohoku.ac.jp.|Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000740:Anemia / Q000235:genetics* / Q000473:pathology; D000818:Animals; D020029:Base Pairing / Q000235:genetics; D001921:Brain / Q000378:metabolism; D017124:Conserved Sequence / Q000235:genetics; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D020964:Embryo Loss / Q000235:genetics / Q000473:pathology; D004921:Erythropoietin / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000378:metabolism; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008822:Mice, Transgenic; D008954:Models, Biological; D009928:Organ Specificity / Q000235:genetics; D011086:Polycythemia / Q000235:genetics / Q000473:pathology; D020218:Response Elements / Q000235:genetics*; D017384:Sequence Deletion; D019076:Transgenes
chemical_list: D004921:Erythropoietin; D049452:Green Fluorescent Proteins
keywords: HIF; HRE; erythropoietin; hypoxia; kidney; renal anemia