A role for the renin-angiotensin system in hematopoiesis

Haematologica (Impact Factor: 5.81). 07/2009; 94(6):745-7. DOI: 10.3324/haematol.2009.006965
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Available from: Tea Soon Park, Oct 02, 2015
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    • "Hence, the local hematopoietic RAS seems to be effective in all species for cellular development. Hematopoiesis [37], myelopoiesis [35], erythropoiesis [38], thrombopoiesis [9], and other cellular lineages [37,39,40,41] are regulated by the actions of the peptides of the local BM RAS. The local BM RAS mediates those complicated networks of BM hematopoiesis in an autocrine/paracrine/intracrine fashion. "
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    ABSTRACT: Objective: The prominent functions of the local renin-angiotensin system (RAS) in primitive hematopoiesis further support the hypothesis that local autocrine bone marrow RAS could also be active in neoplastic hematopoiesis. The aim of this study is to examine critical RAS elements in normal CD34+ hematopoietic stem cells and multiple myeloma (MM)-related progenitor cells. Materials and Methods: The study group comprised the total bone marrow cells (CBM) of 10 hematologically normal people, the CD34+ stem cell samples (CD34+CBM) of 9 healthy donors for allogeneic peripheral stem cell transplantation, and the CD34+ stem cell samples (CD34+MM) of 9 MM patients undergoing autologous peripheral stem cell transplantation. We searched for the gene expression of the major RAS components in healthy hematopoietic cells and myeloma cells by quantitative real-time polymerase chain reaction analysis. Results: RENIN, angiotensinogen (ANGTS), and angiotensin converting enzyme-I (ACE I) mRNA expression levels of CBM were significantly higher than those in myeloma patients (p=0.03, p=0.002, and p=0.0008, respectively). Moreover, RENIN and ANGTS mRNA expression levels were significantly higher in CD34+ stem cell samples of healthy allogeneic donors compared to those in myeloma patients (p=0.001 and p=0.01). However, ACE I expression levels were similar in CD34+CBM and CD34+MM hematopoietic cells (p=0.89). Conclusion: Although found to be lower than in the CBM and CD34+CBM hematopoietic cells, the local RAS components were also expressed in CD34+MM hematopoietic cells. This point should be kept in mind while focusing on the immunobiology of MM and the processing of autologous cells during the formation of transplantation treatment protocols.
    Turkish Journal of Haematology 06/2014; 31(2):136-42. DOI:10.4274/tjh.2013.0011 · 0.36 Impact Factor
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    • "Meanwhile, imidapril significantly decreases CD26 activity in the plasma. ACE inhibitors induce leukopenia in humans and mice [38,55-58], and the leukocyte population is the most abundant source of CD26+ cells in peripheral blood [59,60]. Changes in plasma CD26 levels reflect changes in the levels of this enzyme that are released by the leukocyte population [61], and the reduced CD26 activity levels in the plasma may be secondary to the diminished number of circulating CD26+ cells [62]. "
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    ABSTRACT: Stromal-derived factor (SDF)-1 is a chemokine that recruits bone marrow-derived endothelial precursor cells (EPCs) for choroidal neovascularization (CNV) development. Angiotensin-converting enzyme (ACE) inhibitors mediate the compensatory effects of ACE and CD26/dipeptidyl peptidase IV (DPP IV), which results in the degradation and inactivation of SDF-1 in vivo. ACE inhibitors, such as imidapril, exhibit potential antiangiogenic effects on laser-induced CNV in mice. The role that this imidapril-mediated effect plays in modulating SDF-1 signals has not been defined. The present study assessed the effect of the CD26/SDF-1 signaling pathway on the inhibitory effect of imidapril in CNV development. CNV was induced in C57BL/6J mice by focally rupturing Bruch's membrane using a 532-nm diode laser. The animals were pretreated with PBS, imidapril, diprotin-A (a DPP IV antagonist), or imidapril plus diprotin-A for 5 days before photocoagulation. Treatments were continued daily for 14 days following the laser induction. The normal control group did not undergo laser rupture or receive treatment. CD26 activity was measured using a substrate conversion assay and flow cytometry. SDF-1 levels in both the blood and the bone marrow were measured using an enzyme-linked immunosorbent assay, and the number of circulating endothelial progenitor cells (EPCs) and leukocytes was quantified. Functional analyses of circulating SDF-1 were performed using actin polymerization blood biomarker assays, and the CNV-related responses were evaluated using fluorescein angiography and isolectin-B4-labeled flatmounts. Imidapril directly amplified CD26 activity and had a minor effect on the number of CD26(+) cells in the bone marrow. However, decreased CD26 activity in the plasma was secondary to a decrease in the number of circulating CD26(+) cells and blood leukocytes. Furthermore, imidapril increased SDF-1 concentrations in the peripheral circulation via CD26-induced degradation of SDF-1 in the bone marrow, an effect that coincided with elevated numbers of circulating EPCs. CD26-mediated SDF-1 inactivation was demonstrated by a decrease in SDF-1-induced actin polymerization in the whole blood of imidapril-treated mice. Imidapril markedly decreased angiographic leakage and CNV size. CD26 inhibition completely blocked the CD26/SDF-1 signaling pathway in vivo and reduced the antiangiogenic effect of imidapril. These results strongly suggest that the antiangiogenic effects of imidapril on laser-induced CNV partially involve the modulation of the CD26/SDF-1 signaling pathway.
    Molecular vision 05/2013; 19:1107-21. · 1.99 Impact Factor
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    • "Although it is controversial, the existence of a local bone marrow (BM) RAS has been demonstrated in rats [9]. Because the BM is a highly organized, complex organ, that is, the principal hematopoietic tissue in adults, locally BM-formed Ang II may be an autocrine or paracrine peptide that affects physiological and pathological hematopoiesis [10]. Studies have demonstrated that Ang II plays a role in oxidative stress development in the spontaneously hypertensive rat [11] and in the renovascular hypertensive rat [12]. "
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    ABSTRACT: It has been proposed that the nonhemodynamic effects of angiotensin II are important for the damage observed in the two-kidney, one-clip (2K1C) renovascular hypertension model. Much evidence confirms that angiotensin II is directly involved in NAD(P)H oxidase activation and consequent superoxide anion production, which can damage DNA. The current study was performed to examine the effects of angiotensin-II-dependent hypertension in bone marrow mononuclear cells (BM-MNC); dihydroethidium staining was used to assess reactive oxygen species (ROS) production, and the comet assay was used to assess DNA fragmentation in 2K1C hypertensive mice 14 days after renal artery clipping. In this study we demonstrated that 2K1C hypertensive mice have an elevated lymphocyte count, while undifferentiated BM-MNC counts were diminished. 2K1C mice also showed an augmented ROS production and marked BM-MNC DNA fragmentation. In conclusion, endogenous renin angiotensin system activation-induced arterial hypertension is characterized by excessive ROS production in BM-MNC, which might cause marked DNA damage.
    International Journal of Hypertension 02/2013; 2013:305202. DOI:10.1155/2013/305202
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