Renin–angiotensin system expression in rat bone marrow haematopoietic and stromal cells

Abstract

SummaryThe existence of a bone marrow renin-angiotensin system (RAS) is evidenced by the association of renin, angiotensin converting enzyme (ACE), and angiotensin (Ang) II and its AT 1 and AT 2 receptors with both normal and disturbed haematopoiesis. The expression of RAS components by rat unfractionated bone marrow cells (BMC), haematopoietic-lineage BMC and cultured marrow stromal cells (MSC) was investigated to determine which specific cell types may contribute to a local bone marrow RAS. The mRNAs for angiotensinogen, renin, ACE, and AT 1a and AT 2 receptors were present in BMC and in cultured MSC; ACE2 mRNA was detected only in BMC. Two-colour flow fluorocytometry analysis showed immunodetectable angiotensinogen, ACE, AT 1 and AT 2 receptors, and Ang II, as well as binding of Ang II to AT 1 and AT 2 receptors, in CD4 + , CD11b/c + , CD45R + and CD90 + BMC and cultured MSC; renin was found in all cell types with the exception of CD4 + BMC. Furthermore, Ang II was detected by radioimmunoassay in MSC homogenates as well as conditioned culture medium. The presence of Ang II receptors in both haematopoietic-lineage BMC and MSC, and the de novo synthesis of Ang II by MSC suggest a potential autocrine-paracrine mechanism for local RAS-mediated regulation of haematopoiesis.

Angiotensin II AT1 receptor blockade normalizes CD11b+ monocyte production in bone marrow of hypercholesterolemic monkeys

“…With the objective of identifying a local BM RAS that might function in a hematoregulatory capacity, we previously determined that mRNA and protein for all major components of the RAS were present in BM and that marrow stromal cells have a complete RAS that is capable of generating Ang II. 28 The emerging model of the BM as an ancillary component of atherogenesis is supported by the present study and previous studies in animal models of HC-induced atherosclerosis which exhibited changes in BM consistent with amplified myelopoiesis. Collectively, these data suggest that HC contributes significantly to the functional disruption of BM HSCs.…”

Renovascular Hypertension Leads to DNA Damage and Apoptosis in Bone Marrow Cells

“…Considering that the BM is a highly organized and complex organ system that gives rise to all mature and circulating blood cells, and that BM has been shown to carry a complete RAS (Strawn et al, 2004), it is reasonable to suggest that local Ang II can be responsible for ROS production in the BM of 2K1C hypertensive mice. However, given the ubiquitous nature of the RAS, separating the effects of circulating and localized Ang II is quite difficult.…”

Angiotensin II stimulates arachidonic acid release from bone marrow stromal cells

“…Within the marrow microenvironment, HSC and committed haematopoietic precursors interact with the local MSC, which are crucial to normal bone marrow function in that they provide the majority of necessary growth factors for the regulation of haematopoietic cell development. 18,19 Since human HS-5 MSC express AT 1 -receptor mRNA 15 and we showed that rat MSC express AT 1 -and AT 2 -receptor mRNA and protein, 17 regulation of MSC function may represent an additional pathway by which Ang II influences haematopoiesis. Arachidonic acid (AA), a biologically active fatty acid released by MSC, modulates differentiation of HSC and erythroid and myeloid precursors through eicosanoid metabolites and the production of haematopoietic regulatory factors, 20,21 and may also directly alter the function of HSC.…”

“…Protein for AT 1 -and AT 2 -receptors was analysed by flow cytometry using a 1:100 dilution of rabbit polyclonal antibodies determined by the manufacturer to cross-react with rat and human AT 1 -and AT 2 -receptors (Research Diagnostics, Inc., Flanders, NJ, USA) and which we previously showed detect AT 1 -and AT 2 -receptors in rat MSC. 17 A secondary FITCconjugated anti-rabbit IgG antibody (1:200 dilution) was used as a fluorescent tag; analysis of secondary antibody alone was included as a negative control.…”

“…Recently, we reported the first systematic study of the bone marrow RAS in the rat 17 which included detection of all major RAS components at the mRNA and protein level in various haematopoietic cell lineages and the production of Ang II by marrow stromal cells (MSC). Within the marrow microenvironment, HSC and committed haematopoietic precursors interact with the local MSC, which are crucial to normal bone marrow function in that they provide the majority of necessary growth factors for the regulation of haematopoietic cell development.…”