ANGIOTENSIN-II PARTICIPATES IN MONONUCLEAR CELL RECRUITMENT IN EXPERIMENTAL IMMUNE-COMPLEX NEPHRITIS THROUGH NUCLEAR FACTOR-KAPPA-B ACTIVATION AND MONOCYTE CHEMOATTRACTANT PROTEIN-1 SYNTHESIS

Angiotensin-converting enzyme (ACE) inhibitors reduce macrophage infil tration in several models of renal injury. We approached the hypothesi s that angiotensin II (AngII) could be involved in inflammatory cell r ecruitment during renal damage through the synthesis of monocyte chemo attractant protein-1 (MCP-1). In a model of immune complex nephritis, we observed an up-regulation of renal MCP-1 (mRNA and protein) coincid entally with mononuclear cell infiltration that were markedly reduced by treatment with the ACE inhibitor quinapril. Exposure of cultured ra t mesangial cells to AngII increased MCP-1 mRNA expression (2.7-fold) and synthesis (3-fold), similar to that observed with TNF-alpha. Since NF-kappa B is involved in the regulation of MCP-1 gene, we explored w hether the effects of AngII were mediated through NF-kappa E activatio n. Untreated nephritic rats showed increased renal NF-kappa B activity (3.5-fold) that decreased in response to ACE inhibition. In mesangial cells, AngII activated NF-kappa B (4.3-fold), and the NF-kappa B inhi bitor pyrrolidine dithiocarbamate abolished the AngII-induced NF-kappa B activation and MCP-1 gene expression. Our results suggest that AngI I could participate in the recruitment of mononuclear cells through NF -kappa B activation and MCP-1 expression by renal cells, This could be a novel mechanism that might further explain the beneficial effects o f ACE inhibitors in progressive renal diseases.