Novel GSH analogues (UPF peptides) reduce the oxidative stress in liver of Wfs1-deficient mice

Abstract

Wolfram syndrome 1 (WS) is a rare autosomal recessive neurodegenerative disease, which is characterized by DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness). WS is caused by the mutations in Wolfram syndrome 1 gene (WFS1) encoding transmembrane glycoprotein called wolframin is which primarily located in ER and Wfs1-deficiency causes ER and oxidative stress followed by cell dysfunction [1]. This research concentrates on the influence of NAC and novel GSH analogues (UPF peptides) on the glutathione system on 2- and 6-months old Wfs1-deficient mice livers. The wild-type, heterozygous and knock-out Wfs1 mice were injected with 1 mg/kg i.p. daily for 5 days.The GSH level was higher in 2-months old and lower in 6-months old Wfs1-/- mice compared to wild-type littermates. Furthermore, the glutathione reductase (GR) activity was lower in 2-months old Wfs1-/- mice. Treatment with UPF peptides decreased the GSSG/GSH redox ratio in Wfs1-/- and Wfs1+/+ mice in 2-months old mice and in 6-months old Wfs1-/- mice. Glutathione peroxidase (GPx) activity was decreased after treatment with UPF peptides in 2-months old Wfs1-/- and Wfs1+/+ mice and GR activity increased in Wfs1+/+ mice.