Regulation of Pdx1 by oxidative stress and Nrf2 in pancreatic beta-cells

Abstract

The beta-cell identity gene, pancreatic duodenal homeobox 1 (Pdx1), plays critical roles in many aspects of the life of beta-cells including differentiation, maturation, function, survival and proliferation. High levels of reactive oxygen species (ROS) are extremely toxic to cells and especially to beta-cells due to their relatively low expression of antioxidant enzymes. One of the major mechanisms for beta-cell dysfunction in type-2 diabetes results from oxidative stress-dependent inhibition of PDX1 levels and function. ROS inhibits Pdx1 by reducing Pdx1 mRNA and protein levels, inhibiting PDX1 nuclear localization, and suppressing PDX1 coactivator complexes. The nuclear factor erythroid 2-related factor (Nrf2) antioxidant pathway controls the redox balance and allows the maintenance of high Pdx1 levels. Therefore, pharmacological activation of the Nrf2 pathway may alleviate diabetes by preserving Pdx1 levels.

Keywords: Nrf2; Pdx1; ROS; beta-cells; diabetes; oxidative-stress.

Figure 1

Oxidative stress-dependent pathways affect Pdx1 levels during diabetes. Type-2 diabetes is associated with various pathological conditions that generate ROS, such as hyperglycemia, hyperlipidemia, hypoxia, inflammation, and ER stress. This results in oxidative stress. Oxidative stress reduces the expression level of PLUTO lncRNA, stimulates JNK-dependent FOXO1 activation, inhibits mTOCR signaling, increases SHP expression and reduces FAM3A levels, all of which results in decreased PDX1 levels. On the other hand, in order to maintain ROS at appropriate levels, oxidative stress also serves as a signal for Nrf2 activation by inhibition of Keap1 and by activation of the ERK signaling. This results in increased expression of the Nrf2 target genes, Sod1 and Gpx, which restore PDX1 levels. This figure was generated using BioRender.com.