title: Enhanced erythropoiesis mediated by activation of the renin-angiotensin system via angiotensin II type 1a receptor.
abstract: Although clinical and experimental studies have long suggested a role for the renin-angiotensin system (RAS) in the regulation of erythropoiesis, the molecular basis of this role has not been well understood. We report here that transgenic mice carrying both the human renin and human angiotensinogen genes displayed persistent erythrocytosis as well as hypertension. To identify the receptor molecule responsible for this phenotype, we introduced both transgenes into the AT1a receptor null background and found that the hematocrit level in the compound mice was restored to the normal level. Angiotensin II has been shown to influence erythropoiesis by two means, up-regulation of erythropoietin levels and direct stimulation of erythroid progenitor cells. Thus, we conducted bone marrow transplantation experiments and clarified that AT1a receptors on bone marrow-derived cells were dispensable for RAS-dependent erythrocytosis. Plasma erythropoietin levels and kidney erythropoietin mRNA expression in the double transgenic mice were significantly increased compared with those of the wild-type control, while the elevated plasma erythropoietin levels were significantly attenuated in the compound mice. These results provide clear genetic evidence that activated RAS enhances erythropoiesis through the AT1a receptor of kidney cells and that this effect is mediated by the elevation of plasma erythropoietin levels in vivo.
authors.affiliation: Center for Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kato
authors.forename: Junji
authors.initials: J
authors.lastname: Ishida
authors.forename: Shigehiko
authors.initials: S
authors.lastname: Imagawa
authors.forename: Tomoko
authors.initials: T
authors.lastname: Saito
authors.forename: Norio
authors.initials: N
authors.lastname: Suzuki
authors.forename: Toshiki
authors.initials: T
authors.lastname: Matsuoka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugaya
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanimoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokoo
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohneda
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sugiyama
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yagami
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000809:Angiotensins / Q000737:chemistry / Q000235:genetics; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis; D004921:Erythropoietin / Q000097:blood*; D006400:Hematocrit; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry / Q000502:physiology*; D011945:Receptors, Angiotensin / Q000737:chemistry; D012083:Renin / Q000737:chemistry / Q000235:genetics; D012084:Renin-Angiotensin System; D013234:Stem Cells; D019076:Transgenes; D015854:Up-Regulation
chemical_list: D000809:Angiotensins; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D004921:Erythropoietin; D000804:Angiotensin II; D012083:Renin