title: Cholesterol feeding activates macrophages to upregulate rat mesangial cell fibronectin production.
abstract: BACKGROUND
  Cholesterol feeding has been shown to accelerate the development of glomerulosclerosis in many experimental renal diseases, possibly by promoting the infiltration of macrophages into the glomerulus.
  
  
  METHODS
  In order to assess whether hyperlipidaemia could directly modulate macrophage function to promote glomerulosclerosis, confluent quiescent mesangial cells were exposed to resident (r) or elicited (e) macrophages, from either control (C) or cholesterol-fed (HC) rats or the conditioned media derived from the various macrophage preparations.
  
  
  RESULTS
  All macrophage preparations stimulated mesangial cell fibronectin accumulation over medium alone, but eHC macrophages stimulated significantly greater fibronectin levels. Similarly, all macrophage conditioned media (MPCM) stimulated mesangial cell fibronectin production over medium alone and again the effect was greatest with MPCM derived from eHC macrophages. Proliferation studies using [(3)H]thymidine incorporation demonstrated that all conditioned media, with the exception of rC, stimulated significant mesangial cell proliferation over control levels. TGF-beta and PDGF, pro-fibrogenic growth factors known to be associated with macrophage infiltration, could not be detected in the MPCMs per se. However, they were detected in the culture supernatants of mesangial cells exposed to MPCMs and again secretion was greatest from mesangial cells exposed to eHC-MCPM.
  
  
  CONCLUSIONS
  Monocytes are systemically activated by high serum cholesterol levels so that following maturation to macrophages they elaborate soluble factors that can stimulate mesangial cell fibronectin production, cell proliferation, 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 responses in glomerular mesangial cells.
authors.affiliation: Department of Nephrology, Leicester General Hospital, Leicester, UK.
authors.forename: I Z
authors.initials: IZ
authors.lastname: Pawluczyk
authors.forename: K P
authors.initials: KP
authors.lastname: Harris
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005353:Fibronectins / Q000096:biosynthesis*; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D002791:Cholesterol, Dietary; D017077:Culture Media, Conditioned; D005353:Fibronectins; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol