The role of integrins in IgA nephropathy

The complicated network of immune reactions leading to mesangial cell activation and glomerular sclerosis in IgA nephropathy (IgAN) involves interactions between infiltrating cells, mesangial cells and mesangial matrix which are mediated by adhesion molecules. Integrin expression on mesangial cells in culture has recently been described. In the present work we investigated whether integrin expression on cultured human mesangial cells (MC) and mesangial matrix production could be modulated by mesangial matrix components, or by other proteins which may come into contact with MC during pathologic conditions, such as fibrinogen and von Willebrand factor. Moreover, we evaluated the effects induced by polymeric IgA or aggregated IgA or mixed IgA/IgG aggregates on integrin expression. To elucidate a possible role for abnormally glycosylated IgA, we tested IgA. pretreated with various enzymes specific for carbohydrate residue components of the side carbohydrate chains of IgA molecules. We found that cultured mesangial cells, highly express the av beta 3 integrin receptor for vitronectin and to a lesser extent the alpha 3 beta 1 receptor for fibronectin and collagens. Among these integrins, alpha v beta 3 is modulated by matrix components and particularly enhanced when cells are incubated with proteins which can be abnormally present in the mesangial area, such as fibrinogen, collagen I and von Willebrand factor. IgA and aggregated IgA can modify integrin expression, inducing a decrease in alpha 3 beta 1 and an increase in alpha v expression. Moreover, sugars can affect these interactions, since desialylated IgA enhance the expression of integrin beta 3 chain on cultured mesangial cells and sialic acid per se strongly inhibits it. Conversely, other sugars, represented in the carbohydrate chains of IgA(1) including mannose and N-acetylgalactosamine, were found to enhance alpha v expression. Our data suggest that the interactions of native polymeric IgA, IgA or IgA/IgG aggregates, as well as IgA with altered glycosylation may result in structural rearrangement of mesangial integrins, possibly reflecting on mesangial matrix composition.