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Presence of Diabetic Complications in Type 1 Diabetic Patients Correlates with Low Expression of Mononuclear Cell AGE-Receptor-1 and Elevated Serum AGE

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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.

Materials and 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.

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Acknowledgments

This work was funded in part by the National Institutes of Health (Grant #AG09453). We wish to thank Dr. Andrzej Krolewski for generously providing us with T1D EBV-transformed lymphoblasts and relevant epidemiologic data as well as with helpful advice. The editorial assistance of Ina Katz is greatly appreciated.

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Authors and Affiliations

  1. Division of Experimental Diabetes and Aging, Mount Sinai School of Medicine, Box 1640, One Gustave L. Levy Place, New York, New York, 10029, USA

    Ci-jiang He & Helen Vlassara MD

  2. Diabetes Research Institute, Dusseldorf, Germany

    Theodore Koschinsky & Christina Buenting

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  1. Ci-jiang He
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  2. Theodore Koschinsky
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Correspondence to Helen Vlassara MD.

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He, Cj., Koschinsky, T., Buenting, C. 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, 159–168 (2001). https://doi.org/10.1007/BF03401949

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