title: Deletion of the receptor for advanced glycation end products reduces glomerulosclerosis and preserves renal function in the diabetic OVE26 mouse.
abstract: OBJECTIVE
  Previous studies showed that genetic deletion or pharmacological blockade of the receptor for advanced glycation end products (RAGE) prevents the early structural changes in the glomerulus associated with diabetic nephropathy. To overcome limitations of mouse models that lack the progressive glomerulosclerosis observed in humans, we studied the contribution of RAGE to diabetic nephropathy in the OVE26 type 1 mouse, a model of progressive glomerulosclerosis and decline of renal function.
  
  
  METHODS
  We bred OVE26 mice with homozygous RAGE knockout (RKO) mice and examined structural changes associated with diabetic nephropathy and used inulin clearance studies and albumin:creatinine measurements to assess renal function. Transcriptional changes in the Tgf-beta1 and plasminogen activator inhibitor 1 gene products were measured to investigate mechanisms underlying accumulation of mesangial matrix in OVE26 mice.
  
  
  RESULTS
  Deletion of RAGE in OVE26 mice reduced nephromegaly, mesangial sclerosis, cast formation, glomerular basement membrane thickening, podocyte effacement, and albuminuria. The significant 29% reduction in glomerular filtration rate observed in OVE26 mice was completely prevented by deletion of RAGE. Increased transcription of the genes for plasminogen activator inhibitor 1, Tgf-beta1, Tgf-beta-induced, and alpha1-(IV) collagen observed in OVE26 renal cortex was significantly reduced in OVE26 RKO kidney cortex. ROCK1 activity was significantly lower in OVE26 RKO compared with OVE26 kidney cortex.
  
  
  CONCLUSIONS
  These data provide compelling evidence for critical roles for RAGE in the pathogenesis of diabetic nephropathy and suggest that strategies targeting RAGE in long-term diabetes may prevent loss of renal function.
authors.affiliation: 1Department of Surgery, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA. nr2207@columbia.edu
authors.forename: Nina
authors.initials: N
authors.lastname: Reiniger
authors.forename: Kai
authors.initials: K
authors.lastname: Lau
authors.forename: Daren
authors.initials: D
authors.lastname: McCalla
authors.forename: Bonnie
authors.initials: B
authors.lastname: Eby
authors.forename: Bin
authors.initials: B
authors.lastname: Cheng
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Wu
authors.initials: W
authors.lastname: Qu
authors.forename: Nosirudeen
authors.initials: N
authors.lastname: Quadri
authors.forename: Radha
authors.initials: R
authors.lastname: Ananthakrishnan
authors.forename: Maryana
authors.initials: M
authors.lastname: Furmansky
authors.forename: Rosa
authors.initials: R
authors.lastname: Rosario
authors.forename: Fei
authors.initials: F
authors.lastname: Song
authors.forename: Vivek
authors.initials: V
authors.lastname: Rai
authors.forename: Alan
authors.initials: A
authors.lastname: Weinberg
authors.forename: Richard
authors.initials: R
authors.lastname: Friedman
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Ramasamy
authors.forename: Vivette
authors.initials: V
authors.lastname: D'Agati
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002645:Chickens; D003928:Diabetic Nephropathies / Q000235:genetics / Q000517:prevention & control; D004195:Disease Models, Animal; D017353:Gene Deletion; D005920:Glomerular Mesangium / Q000378:metabolism / Q000473:pathology; D006442:Glycated Hemoglobin / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D011765:Pyruvaldehyde / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency*; D051437:Renal Insufficiency / Q000235:genetics / Q000517:prevention & control
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D011765:Pyruvaldehyde; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic