The glycation reaction (Maillard reaction) plays a major role in
diabetic complications, since some reaction intermediates are responsible for the modification and cross-linking of long-lived
proteins, resulting, in turn, in a deterioration of normal cell function. The reaction intermediates include
methylglyoxal (MG) and
3-deoxyglucosone (3-DG), both of which are cytotoxic dicarbonyl compounds and are elevated during
hyperglycemia.
Aldehyde reductase (ALR) catalyzes the reduction of both compounds. To examine the intracellular role of ALR in the
diabetic complications of neural cells, its gene was overexpressed in rat
pheochromocytoma PC12 cells, which normally express a low level of ALR. Western blot analysis showed that ALR
protein in the ALR gene-transfected cells was more than twice as much as in the control cells. In the parental cells, cytotoxicity, including apoptotic cell death, which was determined by fluorescent microscopy using the fluorescent
DNA binding
dye Hoechst 33258, was observed at 100 microM MG. In the ALR gene-transfected cells, the cytotoxicity of both MG and 3-DG and apoptotic cell death were decreased. This suggests that intracellular ALR protects neural cells from the cytotoxicity of 3-DG or MG, and that neural cells, which normally express a low level of ALR, might be susceptible to
diabetic complications caused by intermediate products of the Maillard reaction, such as 3-DG and MG.