The stress response protein REDD1 promotes diabetes-induced oxidative stress in the retina by Keap1-independent Nrf2 degradation

Abstract

The transcription factor nuclear factor erythroid-2–related factor 2 (Nrf2) plays a critical role in reducing oxidative stress by promoting the expression of antioxidant genes. Both individuals with diabetes and preclinical diabetes models exhibit evidence of a defect in retinal Nrf2 activation. We recently demonstrated that increased expression of the stress response protein regulated in development and DNA damage 1 (REDD1) is necessary for the development of oxidative stress in the retina of streptozotocin-induced diabetic mice. In the present study, we tested the hypothesis that REDD1 suppresses the retinal antioxidant response to diabetes by repressing Nrf2 function. We found that REDD1 ablation enhances Nrf2 DNA-binding activity in the retina and that the suppressive effect of diabetes on Nrf2 activity is absent in the retina of REDD1-deficient mice compared with WT. In human MIO-M1 Müller cell cultures, REDD1 deletion prevented oxidative stress in response to hyperglycemic conditions, and this protective effect required Nrf2. REDD1 suppressed Nrf2 stability by promoting its proteasomal degradation independently of Nrf2's interaction with Kelch-like ECH-associated protein 1 (Keap1), but REDD1-mediated Nrf2 degradation required glycogen synthase kinase 3 (GSK3) activity and Ser-351/Ser-356 of Nrf2. Diabetes diminished inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β) at Ser-9 in the retina of WT mice but not in REDD1-deficient mice. Pharmacological inhibition of GSK3 enhanced Nrf2 activity and prevented oxidative stress in the retina of diabetic mice. The findings support a model wherein hyperglycemia-induced REDD1 blunts the Nrf2 antioxidant response to diabetes by activating GSK3, which, in turn, phosphorylates Nrf2 to promote its degradation.

Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids

“…Pre-decidual cells in SS3 express HAND2 , a key decidual transcription factor ( Marinić et al, 2021 ), as well as previously identified genes encoding secreted factors, including VEGFA (vascular endothelial growth factor A), CRISPLD2 (a progesterone-dependent anti-inflammatory response gene coding cysteine-rich secretory protein LCCL domain containing 2) , IL15 (interleukin 15), and TIMP3 (TIMP metallopeptidase inhibitor 3) ( Lucas et al, 2020 ). Novel candidate pre-decidual genes were also identified, such as DDIT4 (DNA damage-inducible transcript 4), encoding a stress response protein intimately involved in autophagy, stemness, and antioxidative defences ( Ho et al, 2020 ; Miller et al, 2020 ). Decidual cells (SS4) and senescent decidual cells (SS5) express SCARA5 and DIO2 , respectively ( Figure 3E ), two stroma-specific marker genes identified by scRNA-seq analysis of mid- and late-luteal endometrial biopsies ( Lucas et al, 2020 ).…”

Oxidative stress and diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications

“…It has been reported that four classical metabolic abnormalities are involved in hyperglycemia-induced oxidative damages in the retina: activation of the protein kinase C (PKC) pathway; polyol pathway flux; and activation of the hexosamine pathway; intracellular formation of advanced glycation end-products (AGEs) [ 21 , 22 ]. Besides the above metabolic disorders, irregular epigenetic modifications [ 23 ], the abnormal activity of nuclear factors, including highly activated nuclear factor-κB (NF-κB) [ 24 , 25 ] and attenuated activity of Nrf2 (Nrf2 is also called NFE2L2, nuclear factor erythroid 2 related factor 2) [ 26 , 27 ], and hyperglycemia-mediated mitochondrial dysfunction [ 28 ], have also been demonstrated to be correlated with the overproduction of ROS in DR. In particular, oxidative stress caused by epigenetic modifications can last for a long stage, even if blood glucose concentration turns into normal level, which is termed “metabolic memory” [ [29] , [30] , [31] , [32] ].…”

Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids

“…Pre-decidual cells in SS3 express HAND2 , a key decidual transcription factor (Marinic et al, 2021), as well as previously identified genes encoding secreted factors, including VEGFA (vascular endothelial growth factor A), CRISPLD2 (a progesterone-dependent anti-inflammatory response gene coding cysteine rich secretory protein LCCL domain containing 2) , IL15 (interleukin 15) and TIMP3 (TIMP metallopeptidase inhibitor 3) (Lucas et al, 2020). Novel pre-decidual genes were also identified, such as DDIT4 (DNA damage inducible transcript 4), encoding a stress response protein intimately involved in autophagy, stemness and antioxidative defences (Ho et al, 2020, Miller et al, 2020). Decidual cells (SS4) and senescent decidual cells (SS5) express SCARA5 and DIO2 , respectively (Figure 3E), two stroma-specific marker genes identified by scRNA-seq analysis of mid- and late-luteal endometrial biopsies (Lucas et al, 2020).…”