title: Antibody blockade of c-fms suppresses the progression of inflammation and injury in early diabetic nephropathy in obese db/db mice.
abstract: OBJECTIVE
  Macrophage-mediated renal injury plays an important role in the development of diabetic nephropathy. Colony-stimulating factor (CSF)-1 is a cytokine that is produced in diabetic kidneys and promotes macrophage accumulation, activation and survival. CSF-1 acts exclusively through the c-fms receptor, which is only expressed on cells of the monocyte-macrophage lineage. Therefore, we used c-fms blockade as a strategy to selectively target macrophage-mediated injury during the progression of diabetic nephropathy.
  
  
  METHODS
  Obese, type 2 diabetic db/db BL/KS mice with established albuminuria were treated with a neutralising anti-c-fms monoclonal antibody (AFS98) or isotype matched control IgG from 12 to 18 weeks of age and examined for renal injury.
  
  
  RESULTS
  Treatment with AFS98 did not affect obesity, hyperglycaemia, circulating monocyte levels or established albuminuria in db/db mice. However, AFS98 did prevent glomerular hyperfiltration and suppressed variables of inflammation in the diabetic kidney, including kidney macrophages (accumulation, activation and proliferation), chemokine CC motif ligand 2 levels (mRNA and urine protein), kidney activation of proinflammatory pathways (c-Jun amino-terminal kinase and activating transcription factor 2) and Tnf-alpha (also known as Tnf) mRNA levels. In addition, AFS98 decreased the tissue damage caused by macrophages including tubular injury (apoptosis and hypertrophy), interstitial damage (cell proliferation and myofibroblast accrual) and renal fibrosis (Tgf-beta1 [also known as Tgfb1] and Col4a1 mRNA).
  
  
  CONCLUSIONS
  Blockade of c-fms can suppress the progression of established diabetic nephropathy in db/db mice by targeting macrophage-mediated injury.
authors.affiliation: Department of Nephrology, Monash Medical Centre, Clayton, Victoria 3168, Australia.
authors.forename: A K H
authors.initials: AK
authors.lastname: Lim
authors.forename: F Y
authors.initials: FY
authors.lastname: Ma
authors.forename: D J
authors.initials: DJ
authors.lastname: Nikolic-Paterson
authors.forename: M C
authors.initials: MC
authors.lastname: Thomas
authors.forename: L A
authors.initials: LA
authors.lastname: Hurst
authors.forename: G H
authors.initials: GH
authors.lastname: Tesch
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002455:Cell Division / Q000276:immunology; D003928:Diabetic Nephropathies / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D005838:Genotype; D007249:Inflammation / Q000517:prevention & control*; D007684:Kidney Tubules / Q000276:immunology / Q000473:pathology; D020738:Leptin / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D020738:Leptin; D016186:Receptor, Macrophage Colony-Stimulating Factor