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Diabetes 53:743-751, 2004
© 2004 by the American Diabetes Association, Inc.

Divergent Pathways of Gene Expression Are Activated by the RAGE Ligands S100b and AGE-BSA

Jessica V. Valencia1,2, Manisha Mone1, Jin Zhang1, Marla Weetall3, Frank P. Buxton1, and Thomas E. Hughes1

1 Novartis Institutes for BioMedical Research, Cambridge, Massachusetts
2 Department of Molecular Genetics, Microbiology and Immunology, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey
3 PTC Therapeutics, South Plainfield, New Jersey

Activation of the receptor for advanced glycation end products (RAGE) reportedly triggers a variety of proinflammatory responses. However, our previous work revealed that RAGE-binding AGEs free of endotoxin were incapable of inducing vascular cell adhesion molecule-1 (VCAM-1) or tumor necrosis factor-{alpha} (TNF-{alpha}) expression. Thus, the objective of this study was to clarify the role of AGEs in cell activation through gene expression profiling using both in vitro and in vivo model systems. Endothelial cells treated with AGE-BSA, previously shown to bind RAGE with high affinity, did not show gene expression changes indicative of an inflammatory response. In contrast, the alternate RAGE ligand, S100b, triggered an increase in endothelial mRNA expression of a variety of immune-related genes. The effects of AGEs were studied in vivo using healthy mice exposed to two different treatment conditions: 1) intravenous injection of a single dose of model AGEs or 2) four intraperitoneal injections of model AGEs (once per day). In both cases, the liver was extracted for gene expression profiling. Both of the short-term AGE treatments resulted in a moderate increase in liver mRNA levels for genes involved in macrophage-based clearance/detoxification of foreign agents. Our findings using AGEs with strong RAGE-binding properties indicate that AGEs may not uniformly play a role in cellular activation.

Address correspondence and reprint requests to Thomas E. Hughes, Novartis Institutes for BioMedical Research, 100 Technology Square, Bldg. 601/Rm. 5155, Cambridge, MA 02139. E-mail: thomase.hughes{at}pharma.novartis.com


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Copyright © 2004 by the American Diabetes Association.