NRF2: A potential target for the treatment of diabetic nephropathy

Abstract

Abstract One of the major complications of diabetes mellitus is diabetic nephropathy (DN), the pathogenesis of which is primarily driven by oxidative stress. As a major regulator of antioxidant responses, the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) has recently attracted much interest. NRF2 is a primary defense mechanism against the cytotoxic effects of oxidative stress, involving heterogeneous detoxification, the production of antioxidants and anti-inflammatory molecules, DNA repair, nuclear chaperones, and proteasome systems. A myriad of studies in pre-clinical models of DN have consistently demonstrated a beneficial effect of NRF2 activation, suggesting that NRF2 is likely a promising target for treating DN. This has been further supported by findings from clinical trials of bardoxolone methyl, an activator of NRF2, despite the unexpected adverse cardiovascular effects. This review summarizes the support for therapeutic targeting of NRF2 in DN and emphasizes the need for the optimization of NRF2-based treatment with the minimization of potential adverse effects.