title: Presence of diabetic complications in type 1 diabetic patients correlates with low expression of mononuclear cell AGE-receptor-1 and elevated serum AGE.
abstract: BACKGROUND
  Receptors for advanced glycation endproducts (AGE-R) mediate AGE turnover, but can also trigger inflammatory genes that promote diabetic tissue injury and diabetic complications (DC). High AGE levels and reduced AGE-R sites in kidneys of NOD mice prone to type 1 diabetes (T1D) and to renal disease (RD) suggested that impaired AGE-R function may contribute to RD in these mice.
  
  
  METHODS
  In this study, after confirming reduced AGE-R1 expression in NOD mouse peritoneal macrophages, we tested for differences in AGE-R1, -R2, and -R3 gene expression in 54 human subjects by RT-PCR and Western analysis. Fresh peripheral blood mononuclear cells (PBMN) were isolated from 36 persons: 18 T1D patients with severe RD (DC); 11 age-and DM-duration matched patients without DC (n-DC); and 7 normal volunteers (NL). EBV-transformed lymphoblasts were obtained from an additional 18 subjects (12 T1D patients, 6 with and 6 without DC, and 6 nondiabetics).
  
  
  RESULTS
  AGE-R1 mRNA and protein of PBMN from n-DC patients were enhanced (p < .05 versus NL) in proportion to serum AGE levels (sAGE) (p < .005 versus NL). In contrast, PBMN from DC patients exhibited no up-regulation of AGE-R1 mRNA or protein, despite higher sAGE levels (p < .005 versus NL). A similar unresponsiveness in AGE-R1 gene expression was observed in EBV-transformed lymphoblasts from DC patients versus NL (p < .01), but not in n-DC (p = NS). AGE-R2 and -R3 mRNA and protein levels were enhanced in both T1D groups (DC > n-DC) (n-DC AGE-R3, p < .05, DC AGE-R3, p < .05) compared to NL. AGE-R2 mRNA levels correlated with sAGE levels (r = .61, p < .05), and with creatinine clearance (r = -.63, p < .05). No differences were noted in AGE-R2 and -R3 mRNA expression in cultured cells.
  
  
  CONCLUSIONS
  The consistent pattern of elevated serum AGE and low expression of AGE-R1 gene in macrophages from T1D mice (NOD), fresh PBMN and EBV-transformed cells from T1D patients with advanced DC suggests ineffective regulation of R1-mediated AGE turnover, possibly of genetic basis.
authors.affiliation: Division of Experimental Diabetes and Aging, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: He
authors.forename: T
authors.initials: T
authors.lastname: Koschinsky
authors.forename: C
authors.initials: C
authors.lastname: Buenting
authors.forename: H
authors.initials: H
authors.lastname: Vlassara
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000150:complications*; D005260:Female; D017127:Glycation End Products, Advanced / Q000097:blood*; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000097:blood* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic