title: Erythropoiesis and Blood Pressure Are Regulated via AT1 Receptor by Distinctive Pathways.
abstract: The renin-angiotensin system (RAS) plays a central role in blood pressure regulation. Although clinical and experimental studies have suggested that inhibition of RAS is associated with progression of anemia, little evidence is available to support this claim. Here we report that knockout mice that lack angiotensin II, including angiotensinogen and renin knockout mice, exhibit anemia. The anemia of angiotensinogen knockout mice was rescued by angiotensin II infusion, and rescue was completely blocked by simultaneous administration of AT1 receptor blocker. To genetically determine the responsible receptor subtype, we examined AT1a, AT1b, and AT2 knockout mice, but did not observe anemia in any of them. To investigate whether pharmacological AT1 receptor inhibition recapitulates the anemic phenotype, we administered AT1 receptor antagonist in hypotensive AT1a receptor knockout mice to inhibit the remaining AT1b receptor. In these animals, hematocrit levels barely decreased, but blood pressure further decreased to the level observed in angiotensinogen knockout mice. We then generated AT1a and AT1b double-knockout mice to completely ablate the AT1 receptors; the mice finally exhibited the anemic phenotype. These results provide clear evidence that although erythropoiesis and blood pressure are negatively controlled through the AT1 receptor inhibition in vivo, the pathways involved are complex and distinct, because erythropoiesis is more resistant to AT1 receptor inhibition than blood pressure control.
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, 305-8577, Japan; Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kato
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, 305-8577, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Ishida
authors.affiliation: Institute of Medical Sciences, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, 259-1193, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8577, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ishimaru
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, 305-8577, Japan; Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8577, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanimoto
authors.affiliation: Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Ibaraki, 305-8577, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sugiyama
authors.affiliation: Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Ibaraki, 305-8577, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Yagami
authors.affiliation: Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, 305-8577, Japan; Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8577, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
mesh_terms: D000740:Anemia; D000808:Angiotensinogen / Q000235:genetics*; D000818:Animals; D001794:Blood Pressure; D004920:Erythropoiesis / Q000502:physiology*; D004921:Erythropoietin / Q000097:blood / Q000378:metabolism; D006400:Hematocrit; D006579:Heterozygote; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*; D012084:Renin-Angiotensin System; D012156:Reticulocytes / Q000166:cytology / Q000378:metabolism
chemical_list: D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; D004921:Erythropoietin