title: Renal clearance of glycolaldehyde- and methylglyoxal-modified proteins in mice is mediated by mesangial cells through a class A scavenger receptor (SR-A).
abstract: OBJECTIVE
  Glomerular mesangial expansion is a characteristic feature of diabetic nephropathy, and the accumulation of AGE in the mesangial lesion has been implicated as one of its potential causes. However, the route for the AGE accumulation in mesangial lesions in diabetic patients is poorly established.
  
  
  METHODS
  Glycolaldehyde-modified BSA (GA-BSA) and methylglyoxal-modified BSA (MG-BSA) were prepared as model AGE proteins, and their in vivo plasma clearance was examined in mice, and renal uptake by in vitro studies with isolated renal mesangial cells.
  
  
  RESULTS
  Both (111)In-GA-BSA and (111)In-MG-BSA were rapidly cleared from the circulation mainly by both the liver and kidney. Immunohistochemical studies with an anti-GA-BSA antibody demonstrated that intravenously injected GA-BSA accumulated in mesangial cells, suggesting that such cells play an important role in the renal clearance of circulating AGE proteins. Binding experiments at 4 degrees C using mesangial cells isolated from mice showed that (125)I-GA-BSA and (125)I-MG-BSA exhibited specific and saturable binding. Upon incubation at 37 degrees C, (125)I-GA-BSA and (125)I-MG-BSA underwent endocytic degradation by these cells. The binding of the ligands to these cells was inhibited by several ligands for scavenger receptors. The endocytic degradation of GA-BSA by mesangial cells from class A scavenger receptor (SR-A) knock-out mice was reduced by 80% when compared with that of wild-type cells. The glomerular accumulation of GA-BSA after its intravenous administration was attenuated in SR-A knock-out mice, as evidenced by immunohistochemical observations.
  
  
  CONCLUSIONS
  These results raise the possibility that circulating AGE-modified proteins are subjected to renal clearance by mesangial cells, mainly via SR-A. This pathway may contribute to the pathogenesis of AGE-induced diabetic nephropathy.
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nakajou
authors.forename: S
authors.initials: S
authors.lastname: Horiuchi
authors.forename: M
authors.initials: M
authors.lastname: Sakai
authors.forename: N
authors.initials: N
authors.lastname: Haraguchi
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
authors.forename: M
authors.initials: M
authors.lastname: Takeya
authors.forename: M
authors.initials: M
authors.lastname: Otagiri
mesh_terms: D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D000199:Actins / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D005169:Factor VIII / Q000378:metabolism; D005920:Glomerular Mesangium / Q000502:physiology*; D007150:Immunohistochemistry; D007633:Keratins / Q000378:metabolism; D008657:Metabolic Clearance Rate; D051379:Mice; D011506:Proteins / Q000378:metabolism*; D011765:Pyruvaldehyde / Q000493:pharmacokinetics*; D011971:Receptors, Immunologic / Q000502:physiology*; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D012710:Serum Albumin, Bovine / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
chemical_list: D000199:Actins; D011506:Proteins; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D014746:Vimentin; D012710:Serum Albumin, Bovine; D007633:Keratins; D011765:Pyruvaldehyde; D005169:Factor VIII; D000079:Acetaldehyde; C010972:glycolaldehyde