Dissociation of mesangial cell migration and proliferation in experimental glomerulonephritis

Abstract

Background. Recently, we documented that following in vivo mesangial cell (MC) ablation in the Thy1 model, reconstitution of the mesangium occurs by a coordinated proliferation and migration of Thy1 (OX-7)-positive cells originating from the hilus and extraglomerular mesangium. We investigated the role of basic fibroblast growth factor (bFGF) in the mediation of these events. Methods. Rats were injected with antithymocyte serum and 48 hours later were pulsed with 3H-thymidine to label proliferating cells. Ninety minutes later, a baseline renal biopsy was obtained, and rats were injected with neutralizing anti-bFGF antibodies or control IgG. Sacrificial biopsies were obtained at 96 hours of disease. Using computer image analysis, biopsies from both time points were quantitated for the number of radiolabeled MC (proliferation) and their mean distance from the hilus (migration). The effect of bFGF on the migration of MCs in culture was examined using a chemotactic assay. Results. At sacrifice, autoradiographs of rats receiving anti-bFGF had significantly fewer radiolabeled MCs as compared with rats receiving control IgG (8.7 ± 1.9 vs. 14.7 ± 3.5, P = 0.0001), yielding an overall 40% reduction in proliferation. There was no difference, however, in the final distance of radiolabeled MCs from the glomerular hilus in the two groups, indicating that the administration of anti-bFGF did not effect MC migration in this model. In an in vitro chemotactic assay, MCs migrated in response to platelet-derived growth factor (PDGF) BB (20 ng/ml), but did not migrate in response to bFGF at a wide range of concentrations (0.5 to 50 ng/ml). Conclusions. These studies demonstrate that bFGF is an important mediator of MC proliferation but that it does not significantly influence MC migration. This is the first demonstration showing that the mediators effecting proliferation can be dissociated from those mediating migration in renal injury.