Angiotensin III increases MCP-1 and activates NF-kappa B and AP-1 in cultured mesangial and mononuclear cells

Background. Monocyte infiltration is a common feature of renal diseases. An giotensin 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 A ng III is involved in monocyte recruitment through the regulation of the ch emokine, monocyte chemoattractant protein-1 (MCP-1;Northern blot, Western b lot, immunofluorescence, and chemotaxis), and the activation of transcripti on factors, nuclear factor kappa B (NF-kappa B) and activating protein-1 (A P-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-treate d mesangial cells showed increased chemoattractant activity for monocytes, which was partially inhibited by the addition of anti-MCP-1 antibody. Ang I II elicited a rapid NF-kappa B activation (8-fold, after 30 min), showing a kinetics and intensity similar to that observed with Ang II and tumor necr osis factor-alpha. The maximal NF-kappa B activation was correlated with nu clear translocation of p50 and p65 subunits and disappearance of cytosolic I kappa B. Ang III also activated AP-1 (5-fold, after 18 h), while SP-1 was unchanged. Two NF-kappa B inhibitors abolished the Ang III-induced MCP-1 m RNA expression, suggesting that overexpression of this chemokine is mediate d, at least in part, by NF-kappa B activation. Conclusions. Ang III activates the transcription factors NF-kappa B and AP- 1 and increases the expression of related genes, such as MCP-1. Our study d escribes a novel and potent proinflammatory action of this Ang degradation product, expanding the present view of the renin-angiotensin system.