CONICET | Buscador de Institutos y Recursos Humanos

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PERONE Marcelo Javier

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Título:

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

Autor/es:

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

Reunión:

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

Resumen:

Pancreatic β-cells are specializedto 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 triggersexcess production of mitochondrial reactive oxygen species (ROS) that overwhelmthe anti-oxidative capacity of β-cells, leading to oxidative stress. The crosstalkbetween the ER and oxidative stress further contributes to β-cell dysfunction. The inflammatorymicroenvironment of the islet during the autoimmune attack leads to activation of ER stress, oxidative stress, β-cell dysfunctionand 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 enhancedNrf2 transcriptional activity (antioxidant defense pathways) and the expressionof Nrf2 target genes (NQO1, HMOX-1 and Txnrd1) in the rat insulinoma INS-1E (p<0.05). CYT-induced ROS generation was reduced by CpdA inINS-1E cells (p<0.05). CpdA diminished the CYT-induced upregulationof Bax/Bcl-2 ratio (p<0.05) and DP-5 mRNA expression (p<0.05) suggesting a protective effect against CYT-induced apoptosis in INS-1E cells. CpdA protectedagainst the reduction of viabilityand enhanced basal insulin secretion in CYT-challenged INS-1E cells (p<0.05). In summary, we demonstrated that CpdA attenuates oxidative stress and improves viability and function in CYT-challenged b-cells. These results, together with our previous reports on immune cells modulation and the reduction of CYT-triggered β-cell ER stressencourage further research on CpdA as an agent with potent therapeutic activity on autoimmune diabetes.

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