Angiotensin II Type 1a–Deficient Bone Marrow–Derived Dendritic Cells Produce Higher Levels of Monocyte Chemoattractant Protein 1
To the Editor:
We read with interest the article from Crowley et al,1 who studied the role of angiotensin II type 1 (AT1) receptors (AT1aR) on immune cells in the pathogenesis of angiotensin II–induced hypertension by generating bone marrow chimeras with wild-type (WT) donors or donors lacking AT1aR. Interestingly, they found that the group of donors lacking AT1aR had more albuminuria and higher expression of a number of inflammatory mediators, including monocyte chemoattractant protein 1 (MCP-1), with persistent infiltration of macrophages in the kidney, concluding that AT1aR on bone marrow–derived cells had protective actions.
The absence of a functional renin-angiotensin system, like in mice genetically lacking renin, angiotensinogen, angiotensin-converting enzyme, or AT1aR, is associated with microvascular disease and tubulointerstitial inflammation. Ouyang et al2 described that AT1a knockout (KO) mice spontaneously develop glomerular and tubulointerstitial diseases. They observed increased expression of proinflammatory mediators like MCP-1 in renal tissue of AT1a KO mice compared with WT mice. Crowley et al3 studied the role of AT1a in autoimmune glomerulonephritis using MLR-Faslpr/lpr mice. They found that AT1a deficiency accelerated mortality and kidney pathology, showing higher expression of inflammatory mediators, including MCP-1 in the kidneys, when compared with WT mice.
Recruitment of leukocytes plays a crucial role in the progression to irreversible damage in inflammatory states, such as cardiovascular and kidney diseases. Increased expression of MCP-1 is a critical link between angiotensin II and target organ inflammation. Dendritic cells (DCs) are highly specialized antigen-presenting cells with the ability to activate resting T lymphocytes and to initiate primary immune responses. We studied the production of cytokines by bone marrow–derived DCs deficient in AT1aR, AT1bR, or in both AT1 receptors. In line with the reports by Crowley et al,1,3⇓ we found that DCs derived from AT1a KO and double KO mice released significantly higher levels of MCP-1 when compared with control mice. The difference remained significant even after stimulation with lipopolysaccharides (Figure). In contrast, no differences in the production of interleukin 10 and interleukin 12p70 were found between AT1KO-DC and WT-DC (data not shown).
Contrasting with the results described above, Hisada et al4 observed in experimentally induced immune mediated renal injury that glomerular expression, proteinuria, and tissue damage were markedly reduced in AT1aKO mice compared with WT mice. Moreover, Koga et al5 found that AT1a deficiency impaired MCP-1 and vascular cell adhesion molecule 1 expression in the arterial wall in angiotensin II–induced atherogenesis in apolipoprotein E–deficient mice. It seems difficult to reconcile these opposing results, but it is clear that the impact of AT1R on MCP-1 production has been evaluated in different experimental models, and AT1-deficient mice being used in the different experimental settings have been generated by independent KO approaches.
The hypothesis that AT1R may also have “protective effects” based on the findings of Crowley et al1,3⇓ and our findings is surely challenging. Our results support the notion that AT1a isoform activation selectively inhibits MCP-1. We can demonstrate for the first time that, other than the described effects in macrophages, DCs being deficient in AT1a produce more MCP-1. In advance to the approach by Crowley et al,1,3⇓ we also incorporated AT1b and double KO mice that excluded a direct involvement of AT1b in the AT1-mediated MCP-1 regulation.
Sources of Funding
This work was supported by the German Academic Exchange Service (DAAD) bilateral exchange program.
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