Gene doubling increases glyoxalase 1 expression in RAGE knockout mice

• Published in: Biochimica et biophysica acta. General subjects Vol. 1864; no. 1; p. 129438
• Main Authors: Bartling, Babett, Zunkel, Katja, Al-Robaiy, Samiya, Dehghani, Faramarz, Simm, Andreas
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.01.2020
• Subjects: Advanced glycation end-products; animal models; blood cells; brain; chromosomes; Copy number variation; Dnahc8; enzymes; females; gene expression regulation; genes; genetic variance; genomics; Glo1; heart; immune response; kidneys; knockout mutants; ligands; liver; lungs; males; mice; polymerase chain reaction; Receptor for advanced glycation end-products; Sex; spleen; tissues; transgenic animals; Advanced glycation end-products; Copy number variation; Dnahc8; Receptor for advanced glycation end-products; Glo1; Sex
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2019.129438

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. 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. 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. A genetic variance in RAGE-KO mice falsely suggests an interaction of RAGE and Glo1 function. RAGE-independent up-regulation of Glo1 in RAGE-KO mice might be as another explanation for, at least some, effects attributed to RAGE before. •RAGE interacts with methylglyoxal-derived AGEs, which are reduced by Glo1 activity.•Glo1 expression and activity are up-regulated in tissues of RAGE knockout mice.•Glo1 up-regulation is not caused by RAGE deficiency but Glo1 copy number variation.•Glo1 expression and activity in some tissues are additionally increased in males.•Effects attributed to RAGE could be caused by Glo1 up-regulation in these mice.