Angiotensin III increases MCP-1 and activates NF-kappaB and AP-1 in cultured mesangial and mononuclear cells.

BACKGROUND: Monocyte infiltration is a common feature of renal diseases. Angiotensin II (Ang II) participates in inflammatory cell infiltration in the kidney. However, the influence of other peptides of the renin-angiotensin system, such as the N-terminal Ang II degradation product Ang III, has not been addressed.
METHODS: In cultured renal and mononuclear cells, we investigated whether Ang III is involved in monocyte recruitment through the regulation of the chemokine, monocyte chemoattractant protein-1 (MCP-1; Northern blot, Western blot, immunofluorescence, and chemotaxis), and the activation of transcription factors, nuclear factor kappaB (NF-kappaB) and activating protein-1 (AP-1; electrophoretic mobility shift assay).
RESULTS: In cultured rat mesangial and mononuclear cells, Ang III increased MCP-1 gene expression and protein levels. Supernatants from Ang III-treated mesangial cells showed increased chemoattractant activity for monocytes, which was partially inhibited by the addition of anti-MCP-1 antibody. Ang III elicited a rapid NF-kappaB activation (8-fold, after 30 min), showing a kinetics and intensity similar to that observed with Ang II and tumor necrosis factor-alpha. The maximal NF-kappaB activation was correlated with nuclear translocation of p50 and p65 subunits and disappearance of cytosolic IkappaB. Ang III also activated AP-1 (5-fold, after 18 h), while SP-1 was unchanged. Two NF-kappaB inhibitors abolished the Ang III-induced MCP-1 mRNA expression, suggesting that overexpression of this chemokine is mediated, at least in part, by NF-kappaB activation.
CONCLUSIONS: Ang III activates the transcription factors NF-kappaB and AP-1 and increases the expression of related genes, such as MCP-1. Our study describes a novel and potent proinflammatory action of this Ang degradation product, expanding the present view of the renin-angiotensin system.