Nrf2 Activators as Attractive Therapeutics for Diabetic Nephropathy

Abstract

Diabetes is the major cause of chronic kidney disease worldwide (1) with treatment options focused primarily on glucose control, blood pressure, lipid lowering, and the blockade of the renin-angiotensin system (2). However, despite intensive metabolic control and other interventions (3), the unrelenting decline in kidney function means that for many patients the condition progresses to overt kidney failure. This underpins the urgent need for novel approaches to manage the ever-increasing number of patients with diabetes and chronic kidney disease. One approach that is attracting attention is the use of compounds to bolster the natural cytoprotective responses of the body. The transcription factor NF-E2–related factor 2 (Nrf2), together with its negative regulator, Kelch-like ECH-associated protein 1 (Keap1), is considered one of the most important cellular defense mechanisms to combat oxidative stress (4) with a particular role in the regulation of phase II detoxifying enzymes (Fig. 1). In particular, NADPH quinone oxidoreductase, glutathione S -transferase, heme oxygenase-1, and γ-glutamylcysteine synthetase are well-studied targets of Nrf2 that are upregulated through the antioxidant response element found in the promoters of these genes (5). Therefore, the coordinated upregulation of genes coding for detoxification, antioxidant, and anti-inflammatory regulators is seen as a potential therapeutic strategy to protect against insults such as inflammation and oxidative stress that are …