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.

Predictors of functional capacity in younger and elderly chronic heart failure patients: An observational study

“…In patients with CHF, increased RDW might especially be associated with nutritional anemia, inflammation, renal insufficiency, ineffective erythropoesis and oxidative stress (26,27). In addition, neurohormonal activation seems to be associated with increased erythropoesis, thus increasing the RDW values (13). In a recent study, a strong and independent association between RDW and inflammatory markers was demonstrated in a large cohort (28).…”

“…In patients with CHF, increased RDW seems to be associated with malnutrition, inflammation, renal insufficiency, and ineffective erythropoiesis (6). Furthermore, increased RDW may be a finding of increased erythropoiesis related to neurohormonal activation (13). However, the exact mechanisms underlying the association of increased RDW and adverse outcomes in patients with CHF are not completely explained.…”

Deterioration of atherosclerosis in mice lacking angiotensin II type 1A receptor in bone marrow-derived cells

“…BM cells were harvested from male donor WT or AT1-KO mice. 24 One THM group received BM cells from male donor WT mice (designated as THM'WT), while the second THM group received cells from male donor AT1-KO mice (designated as THM'AT1-KO). As a control, irradiated female WT mice also received BM cells from male donor WT mice (designated as WT'WT).…”

“…At 14 weeks of age, genotype exchange was confirmed as described previously. 24 Measurement of BP Systolic BP was measured using a non-invasive computerized tail cuff BP system on awake animals (BP-98A; Softron, Japan) as described previously. 19 Serum Blood Urea Nitrogen Analysis and Urinary Albumin Analysis Prior to killing, mice were deprived of food for 8 h. Mice were anesthetized with diethylether and blood samples were collected by cardiac puncture.…”

“…24 In the first set of BMT experiments, animals were challenged with an atherogenic diet for 14 weeks. Survival rates of both THM groups were significantly lower than that of the WT'WT group (THM'WT (n ¼ 31), 59.4%; THM'AT1-KO (n ¼ 21), 33.3% and WT'WT (n ¼ 13), 92.3% at age 28 weeks).…”