Presence of diabetic complications in type 1 diabetic patients correlates with low expression of mononuclear cell AGE-receptor-1 and elevated serum AGE
Cj. He et al., Presence of diabetic complications in type 1 diabetic patients correlates with low expression of mononuclear cell AGE-receptor-1 and elevated serum AGE, MOL MED, 7(3), 2001, pp. 159-168
Citations number
45
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research General Topics
Background: Receptors for advanced glycation endproducts (AGE-R) mediate AG
E turnover, but can also trigger inflammatory genes that promote diabetic t
issue injury and diabetic complications (DC). High AGE levels and reduced A
GE-R sites in kidneys of NOD mice prone to type 1 diabetes (TID) and to ren
al disease (RD) suggested that impaired AGE-R function may contribute to RD
in these mice.
Materials and Methods: In this study, after confirming reduced AGE-R1 expre
ssion in NOD mouse peritoneal macrophages, we tested for differences in AGE
-RI, -R2, and -R3 gene expression in 54 human subjects by RT-PCR and Wester
n analysis. Fresh peripheral blood mononuclear cells (PBMN) were isolated f
rom 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-tran
sformed lymphoblasts were obtained from an additional 18 subjects (12 T1D p
atients, 6 with and 6 without DC, and 6 nondiabetics).
Results: AGE-RI mRNA and protein of PBMN from n-DC patients were enhanced (
p <.05 versus NL) in pro- portion to serum AGE levels (sAGE) (p <.005 versu
s NL). In contrast, PBMN from DC patients exhibited no up-regulation of AGE
-Ri mRNA or protein, despite higher sAGE levels (p <.005 versus NL). A simi
lar unresponsiveness in AGE-RI gene expression was observed in EBV-transfor
med 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 group
s (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 creat
inine 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 expressio
n of AGE-RI gene in macrophages from T1D mice (NOD), fresh PBMN and EBV-tra
nsformed cells from T1D patients with advanced DC suggests ineffective regu
lation of R1-mediated AGE turnover, possibly of genetic basis.