Diabetes and Pi Class Glutathione S-Transferase

OLIVERI, LEDA MARIA; MORA, SANDRA; BUZALEH ANA MARIA; GEREZ ESTHER

New Innovations in Chemistry and Biochemistry

BPInternational

Lugar: Londres; Año: 2022; p. 137 - 153

Diabetes mellitus is characterized by chronic hyperglycemia caused by defects in the secretion and/or action of insulin. Hyperglycemia generates free radicals producing oxidative stress, which debilitates the endogenous antioxidant defense system. Oxidative stress is a key factor that contributes with the development of diabetes complications. Glutathione S-transferases (GSTs) are a multigene superfamily of enzymes that catalyze the conjugation of glutathione with electrophilic compounds including those produced during oxidative stress. Pi-class GST (GSTP), one of the GST isoenzymes, has a particular high affinity for small unsaturated aldehydes. The expression and activity of GSTs during diabetes have been extensively studied, but little is known about regulation mechanisms of GSTP. The 5?-regulatory region of mouse GSTP gene contains binding sites for the transcription factors, the activator protein-1 (AP1) and the Specificity protein 1 (Sp1). The aim of the present study was to evaluate how GSTP is regulated in a Streptozotocin (STZ)-induced murine diabetes model. GSTs activity and GSTP expression were determined in adult male mice diabetized with STZ. Sp1 expression and O-glycosylation, as well as the role of AP-1 members Jun and Fos in the regulation of GSTP expression, were also assessed. The results showed that GSTs total activity and GSTP mRNA and protein levels were decreased in the diabetic liver, and returned to normal values after insulin administration. The insulin-mimetic drug vanadate was also able to restore GSTs activity, but failed to recover GSTP mRNA/protein levels. When the animals received vitamin E, both GSTs activity and GSTP mRNA were partially restored. In diabetic animals, O-glycosylated Sp1 levels were increased, whereas, in insulin-treated animals, glycosylation values were similar to those of controls. After vanadate administration, Sp1 expression levels and glycosylation were lower than those of controls. Our results suggest that hyperglycemia could lead to the observed increase in Sp1 O-glycosylation, which would, in turn, lead to a decrease in the expression of Sp1-dependent GSTP in the liver of diabetic mice.