Upregulation of renin-angiotensin system during differentiation of monocytes to macrophages

Background We have demonstrated that accumulated macrophages in human coron ary arteries strongly express angiotensin converting enzyme in accordance w ith the development of atheromatous plaques. However, there are few reports on the regulation of the renin-angiotensin system in macrophages and in mo nocytes as their source. Objective To examine whether the renin-angiotensin system is upregulated du ring the differentiation of monocytes to macrophages, and whether it is fur ther regulated by angiotensin II and cytokines. Materials and methods We used a human leukemia cell line, THP-1, for monocy tes. Differentiated THP-1, induced by adding phorbol 12-myristate 13-acetat e for 24 h, were used as macrophages. Expression of messenger RNA of the re nin-angiotensin system components was measured by quantitative reverse-tran scriptase polymerase chain reaction. Angiotensin converting enzyme activity and subtype-specific angiotensin-binding sites of cultured cells, and angi otensin II production in the culture medium were measured. Results Macrophages expressed all components of the renin-angiotensin syste m except chymase. Cellular angiotensin converting enzyme activity and angio tensin II in the medium were increased 3.2- and 4.5-fold during differentia tion, respectively, Expression of angiotensin II type 1 (AT(1)) and type 2 (AT(2)) receptors was increased 6.2- and 6.4-fold during differentiation, a nd was sustained for 7 days. Incubation with angiotensin II for 24 h caused downregulation of both AT(1) and AT(2) receptor messenger RNA, but the exp ression levels were still more than threefold higher compared with monocyte s. The density of binding sites of AT(1) and AT(2) receptors in macrophages was 0.26 +/- 0.02 and 0.15 +/- 0.01 fmol/10(6) cells, respectively. Conclusion The renin-angiotensin system is markedly activated during monocy te/macrophage differentiation, and may participate in the development of at herosclerosis. J Hypertens 1999, 17:537-545 (C) Lippincott Williams & Wilki ns.