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

Abstract

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. 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). 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. 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.