Involvement of angiotensin II and type 1 receptors in the bacterial endotoxin-induced activation of microglial cells

We investigated whether angiotensin II (ANG II) and its receptors contributes to lipopolysaccharide (LPS)-induced microglial activations through their effect on the activation of proinflammatory transcription factors, NF-kB and AP-1. To this end, examined were the effects of an ANG type 1 receptor (AT1) antagonist, losartan, on the LPS-induced productions of interleukin-1 (IL-1) and nitric oxide (NO), morphological changes of the cells, as well as the activations of NF-kB and AP-1 in primary culture of microglial cells. Our RT-PCR study revealed that LPS-stimulated microglial cells had marked expression of mRNAs for AT1 and angiotensinogen. LPS (100 ng/ml)-stimulated microglial cells showed increases in IL-1 and nitrite (a relatively stable metabolite of NO) concentrations, and in the expression of IL-1 mRNA, as well as a morphological change from an amoeboid shape to a multipolar (mostly bipolar, but sometimes tripolar) rod shape. These effects were all significantly inhibited by treatment with AT1 antagonist, losartan. The activity of NF-kB and AP-1 was enhanced in LPS-stimulated microglia, that were significantly suppressed by losartan. Application of ANG II itself enhanced the LPS-induced increase in nitrite concentration, that were inhibited by losartan. These results suggest that ANG II enhances microglial activities through the stimulation of microglial receptor, AT1, which evokes activation of transcription factors, NF-kB and AP-1. [J Physiol Sci. 2008;58 Suppl:S105]