Enhanced erythropoiesis mediated by activation of the renin-angiotensin system via angiotensin II type 1a receptor.
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.
Kato
Hideki
H
Center for Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, Japan.
Ishida
Junji
J
Imagawa
Shigehiko
S
Saito
Tomoko
T
Suzuki
Norio
N
Matsuoka
Toshiki
T
Sugaya
Takeshi
T
Tanimoto
Keiji
K
Yokoo
Takashi
T
Ohneda
Osamu
O
Sugiyama
Fumihiro
F
Yagami
Ken-ichi
K
Fujita
Toshiro
T
Yamamoto
Masayuki
M
Nangaku
Masaomi
M
Fukamizu
Akiyoshi
A
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
D000809:Angiotensins; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D004921:Erythropoietin; D000804:Angiotensin II; D012083:Renin