Combating oxidative stress in diabetic complications with Nrf2 activators: how much is too much?

Abstract

Diabetes is increasing at an alarming rate and, despite anti-hypertensive and insulin therapies, diabetic patients are still at risk of developing complications such as chronic kidney disease, cardiovascular disease, and retinopathy. There is therefore an urgent need for more effective therapies to prevent the development and progression of diabetic complications. Oxidative stress is a major player in the aetiology of diabetic complications. However, results from clinical trials thus far using general antioxidants have been disappointing. Mechanism-based antioxidants have gained considerable attention due to their more targeted approach at reducing oxidative stress and associated complications in diabetes. The transcription factor, NFE2-related factor 2 (Nrf2), is a master regulator of redox homeostasis and the cellular detoxification response. Instead of relying on a single antioxidant, activation of Nrf2 results in the concerted upregulation of several antioxidant enzymes and cytoprotective genes, making it an attractive therapeutic target for diabetic complications. Several Nrf2 activators have been discovered and have proven effective at activating Nrf2 signalling through different mechanisms in both in vitro and in vivo models of diabetes. This review will address some of the most promising and well-known Nrf2 activators and their roles in preventing the development and progression of diabetic complications. Challenges facing the advancement of this drug class into the clinic will be discussed, as will be the future of Nrf2 activation as a therapeutic strategy in preventing the development of diabetic complications.

Keywords: Antioxidant defence; Diabetes-associated atherosclerosis; Diabetic complications; Diabetic nephropathy; Mouse models; Nrf2 activators; Oxidative stress.

Figure 1.

The role of Nrf2 signalling in diabetic complications. Hyperglycaemia is associated with the generation of reactive oxygen species (ROS) by the mitochondria and angiotensin II (Ang II)-induced activation of NOX. Ang II and ROS can activate the NFκB pathway leading to transcription of fibrotic and inflammatory genes such as TGF-β, MCP1 and TNF-α, resulting in diabetic complications. Under normal conditions, Nrf2 is constitutively targeted by its negative regulator, Keap1, for ubiquitination and degradation in the cytosol. On the other hand, hyperglycaemia-induced oxidative stress stabilizes Nrf2 by releasing Keap1 binding, allowing Nrf2 to translocate to the nucleus where it activates ARE-responsive genes, such as HO-1, NQO1, SOD, and CAT. These antioxidant and cytoprotective genes reduce ROS levels, leading to an attenuation of diabetic complications.

Figure 2.

The proposed mechanisms of Nrf2 activators. Bardoxolone methyl, dh404, and sulforaphane interact with cysteine thiol residues on Keap1, the negative regulator of Nrf2. This interaction leads to the dissociation and stabilization of Nrf2, allowing it to translocate to the nucleus and bind to the antioxidant response element (ARE) in the promoter region of antioxidant and cytoprotective genes, leading to the transcription of these genes. On the other hand, MG132 inhibits proteasomal activity thereby preventing the degradation of Nrf2 leading to the increased accumulation of Nrf2 in the nucleus and activation of ARE-responsive genes. The mechanism of resveratrol is less well understood but it is proposed to increase expression and translocation of Nrf2 to the nucleus, possibly by decreasing the expression of Keap1.