title: Possible mechanism for medial smooth muscle cell injury in diabetic nephropathy: glycoxidation-mediated local complement activation.
abstract: BACKGROUND
  Although recent studies have emphasized the pathogenic role of intrarenal muscular arteries in patients with diabetic nephropathy, notice has not been taken of their pathological characteristics. We focused on medial smooth muscle cell (SMC) injury and the involvement of glycoxidation and complement activation.
  
  
  METHODS
  Renal samples were obtained at autopsy from patients with diabetes mellitus (DM), patients with hypertension without renal involvement (n = 9), patients with benign nephrosclerosis (n = 7), and age-matched control subjects (n = 12). Patients with DM had glomerulosclerosis classified as severe (n = 9; DM-sev), moderate (n = 11; DM-mod), and minimal (n = 7). Renal samples were immunohistochemically determined. Activation of plasma complement from healthy subjects using advanced glycation end products (AGEs) also was performed.
  
  
  RESULTS
  A marked SMC loss was noted in the media of patients with DM-sev and DM-mod. A membrane attack complex (MAC) observed in the area with SMC loss correlated well with the loss. Considerable carboxymethyllysine (CML), an oxidatively modified AGE, was deposited in the area with SMC loss in patients with DM-mod and DM-sev. Degrees of MAC deposition, SMC loss, and CML deposition were greater in the DM-sev group than the non-DM groups. Another oxidative product, acrolein, colocalized with CML. Plasma complements were not activated by AGE-modified bovine serum albumin in our in vitro assays, which included a complement hemolytic activity assay and determination of complement fragments, including C4d, C3bB, iC3b, and MAC.
  
  
  CONCLUSIONS
  It is strongly suggested that medial SMC injury in intrarenal arteries is caused by interaction between glycoxidation and complement activation and contributes to the progression of diabetic nephropathy.
authors.affiliation: Department of Pathology, School of Medicine, Fukuoka University, Fukuoka, Japan. nouesugi@fukuoka-u.ac.jp
authors.forename: Noriko
authors.initials: N
authors.lastname: Uesugi
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sakata
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Abe
authors.forename: Seikoh
authors.initials: S
authors.lastname: Horiuchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hisano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwasaki
mesh_terms: D000171:Acrolein / Q000032:analysis; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001161:Arteriosclerosis / Q000150:complications / Q000378:metabolism / Q000473:pathology; D003167:Complement Activation; D015938:Complement Membrane Attack Complex / Q000032:analysis; D003928:Diabetic Nephropathies / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000150:complications / Q000378:metabolism / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000032:analysis*; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000473:pathology; D007668:Kidney / Q000098:blood supply*; D007678:Kidney Glomerulus / Q000737:chemistry / Q000473:pathology; D008239:Lysine / Q000031:analogs & derivatives* / Q000032:analysis; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009400:Nephrosclerosis / Q000150:complications / Q000473:pathology; D010084:Oxidation-Reduction; D017540:Tunica Media / Q000473:pathology*
chemical_list: D015938:Complement Membrane Attack Complex; D017127:Glycation End Products, Advanced; C048496:N(6)-carboxymethyllysine; D000171:Acrolein; D008239:Lysine