Activation of NRF2 pathway by compound A protects against oxidative stress and β-cell dysfunction

FUERTES, F; PERONE, MJ; ANDREONE, L; DE BOSSCHER, K; ARIOLFO, L

Mar del Plata

Congreso; Reunión Conjunta de SAIC, SAFE, y SAP; 2019

Sociedad Argentina de Investigación Clínica

Pancreatic β-cells are specialized to secrete insulin in response to circulating nutrients, mainly glucose. Type 1 diabetes is a T cell-mediated autoimmune disease that selectively destroys β-cells; both ER stress and subsequent insulin secretory deficiency precede the onset of disease. Hyperglycemia triggers excess production of mitochondrial reactive oxygen species (ROS) that overwhelm the anti-oxidative capacity of β-cells, leading to oxidative stress. The crosstalk between the ER and oxidative stress further contributes to β-cell dysfunction. The inflammatory microenvironment of the islet during the autoimmune attack leads to activation of ER stress, oxidative stress, β-cell dysfunction and death. We reported that Compound A (CpdA), a dissociative glucocorticoid receptor-ligand, is an effective modulator of T and dendritic cells and ameliorates cytokine (IL-1b+IFN-g; CYT)-induced ER stress in β-cells. The aim of this study was to explore the protective effects of CpdA on CYT-induced β-cell oxidative stress. CpdA enhanced Nrf2 transcriptional activity (antioxidant defense pathways) and the expression of Nrf2 target genes (NQO1, HMOX-1 and Txnrd1) in the rat insulinoma INS-1E (p