Methylglyoxal-Lysine Dimer, an Advanced Glycation end Product, Induces Inflammation via Interaction with RAGE in Mesangial Cells.

SCOPE Advanced glycation end products (AGEs) and receptor of advanced glycation end products (RAGE) mediate renal function during diabetic and non-diabetic nephropathy development. Methylglyoxal-lysine dimer (MOLD), a typical toxic advanced glycation end product (TAGE), contributes to inflammatory responses during renal diseases. We determined the effect of MOLD on inflammatory responses in mouse mesangial cells. METHODS AND RESULTS The murine mesangial cell line SV40 MES13 was used to assess nuclear factor-kappa B (NF-κB) expression, reactive oxygen species (ROS) production, and mitochondria labeling. The interaction model between RAGE and MOLD was also determined. MOLD treatment of mesangial cells markedly increased RAGE expression and the linkage with V-type Ig domain of RAGE. MOLD induced ROS production and mitochondrial dysfunction. MOLD activated phosphatidylinositol 3-kinase-protein kinase B (PI3KB) and NF-κB signaling pathways. It was confirmed that these changes were reversed when ROS was suppressed. These effects may be regulated through mitogen-activated protein kinases and pro-inflammatory cytokines in circulatory inflammation responses. CONCLUSION MOLD plays a major role in nephropathy via ROS production and mitochondrial dysfunction through direct association with RAGE. Further, the NF-kB and PI3k/AKT signaling pathways triggered by ROS mediate the inflammatory response to exacerbate MOLD-induced damages in inflammation-related diabetic and non-diabetic renal diseases. This article is protected by copyright. All rights reserved.