Cholesterol feeding activates macrophages to upregulate rat mesangial cellfibronectin production

Background. Cholesterol feeding has been shown to accelerate the developmen t of glomerulosclerosis in many experimental renal diseases, possibly by pr omoting the infiltration of macrophages into the glomerulus. Methods. In order to assess whether hyperlipidaemia could directly modulate macrophage function to promote glomerulosclerosis, confluent quiescent mes angial cells were exposed to resident (r) or elicited (e) macrophages, from either control (C) or cholesterol-fed (HC) rats or the conditioned media d erived from the various macrophage preparations. Results. All macrophage preparations stimulated mesangial cell fibronectin accumulation over medium alone, but eHC macrophages stimulated significantl y greater fibronectin levels. Similarly, all macrophage conditioned media ( MPCM) stimulated mesangial cell fibronectin production over medium alone an d again the effect was greatest with MPCM derived from eHC macrophages. Pro liferation studies using [H-3]thymidine incorporation demonstrated that all conditioned media, with the exception of rC, stimulated significant mesang ial cell proliferation over control levels. TGF-beta and PDGF, pro-fibrogen ic growth factors known to be associated with macrophage infiltration, coul d not be detected in the MPCMs per se. However, they were detected in the c ulture supernatants of mesangial cells exposed to MPCMs and again secretion was greatest from mesangial cells exposed to eHC-MCPM. Conclusion. Monocytes are systemically activated by high serum cholesterol levels so that following maturation to macrophages they elaborate soluble f actors that can stimulate mesangial cell fibronectin production, cell proli feration, and growth factor secretion. Hypercholesterolaemia may therefore accelerate glomerulosclerosis not only by increasing macrophage number, but also by upregulating the ability of macrophages to induce pro-sclerotic re sponses in glomerular mesangial cells.