Background: The receptor for advanced glycation end-products (RAGE) is a multifunctional protein. Its function as pattern recognition receptor able to interact with various extracellular ligands is well described. Genetically modified mouse models, especially the RAGE knockout (RAGE-KO) mouse, identified the amplification of the immune response as an important function of RAGE. Pro-inflammatory ligands of RAGE are also methylglyoxal-derived advanced glycation end-products, which depend in their quantity, at least in part, on the activity of the methylglyoxal-detoxifying enzyme glyoxalase-1 (Glo1). Therefore, we studied the potential interaction of RAGE and Glo1 by use of RAGE-KO mice.

Methods: Various tissues (lung, liver, kidney, heart, spleen, and brain) and blood cells from RAGE-KO and wildtype mice were analyzed for Glo1 expression and activity by biochemical assays and the Glo1 gene status by PCR techniques.

Results: We identified an about two-fold up-regulation of Glo1 expression and activity in all tissues of RAGE-KO mice. This was result of a copy number variation of the Glo1 gene on mouse chromosome 17. In liver tissue and blood cells, the Glo1 expression and activity was additionally influenced by sex with higher values for male than female animals. As the genomic region containing Glo1 also contains the full-length sequence of another gene, namely Dnahc8, both genes were duplicated in RAGE-KO mice.

Conclusion: A genetic variance in RAGE-KO mice falsely suggests an interaction of RAGE and Glo1 function.

General significance: RAGE-independent up-regulation of Glo1 in RAGE-KO mice might be as another explanation for, at least some, effects attributed to RAGE before.