The Maillard reaction product N^ϵ-Carboxymethyl-L-lysine induces heat shock proteins 72 and 90α via RAGE interaction in HEK-293 cells

Thermal treatment of foods leads to browning through the generation of Maillard reaction products (MRPs). In addition to their generation in vivo, ingestion of foods high in MRPs may contribute to an accumulation of glycation products in tissues, named advanced glycation endproducts (AGEs). Increased plasma and tissue concentrations of AGEs have been associated with aging processes, and the progression of several diseases such as diabetes mellitus and Alzheimer's disease. However, in non-pathological conditions, high AGE levels are not observed, indicating cellular mechanisms counteracting AGE accumulation. In this study, we investigated the effect of N^ϵ-Carboxymethyl-L-lysine (CML), a well-characterized product of the Maillard reaction, on the protein expression of heat shock proteins 72 and 90α in HEK-293 cells and HEK-293 cells expressing only the extracellular domain of the receptor for AGEs (RAGE). In HEK-293 cells expressing full length RAGE, CML treatment resulted in an increase of heat shock protein 72 (Hsp72) and heat shock protein 90α (Hsp90α) expression in contrast to cells lacking the receptor's cytosolic domain, indicating a RAGE-mediated mechanism. Furthermore, in HEK-293 cells exposed to repeated mild heat shocks (RMHS), high protein levels of Hsp72 and Hsp90α were associated with protective effects against the accumulation of CML and its formation from glyoxal. In cells treated with RMHS after CML exposure, a reduction of the cellular CML concentration to 91.8 ± 0.7% in relation to CML treatment only (set to 100%) was observed. Inversion of the treatment order, i.e. RMHS prior to CML treatment, resulted in an even greater reduction of the cellular CML concentration to 75.2 ± 6.1% in relation to CML treatment only. Therefore, HSPs might counteract CML accumulation, and thereby help to prevent increasing CML tissue concentrations in physiological states.