Protective Role of Nrf2 in Renal Disease

Abstract

Chronic kidney disease (CKD) is one of the fastest-growing causes of death and is predicted to become by 2040 the fifth global cause of death. CKD is characterized by increased oxidative stress and chronic inflammation. However, therapies to slow or prevent CKD progression remain an unmet need. Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that plays a key role in protection against oxidative stress and regulation of the inflammatory response. Consequently, the use of compounds targeting Nrf2 has generated growing interest for nephrologists. Pre-clinical and clinical studies have demonstrated that Nrf2-inducing strategies prevent CKD progression and protect from acute kidney injury (AKI). In this article, we review current knowledge on the protective mechanisms mediated by Nrf2 against kidney injury, novel therapeutic strategies to induce Nrf2 activation, and the status of ongoing clinical trials targeting Nrf2 in renal diseases.

Keywords: Nrf2; acute kidney injury; and inflammatory response; oxidative stress; renal disease.

Figure 1

Schematic structure of Nrf2. Nrf2 has seven highly conserved domains (Neh1-Neh7). Among these domains, Neh2 is the Keap1-binding domain. Neh6 is important for binding to the negative regulator β-TrCP. Both Neh2 and Neh5 are responsible for Nrf2 ubiquitination and degradation. Neh1 contains a cap‘n’collar basic-region leucine zipper domain that is important for interacting with sMAF proteins and DNA, and is also required for the nuclear translocation of Nrf2. Neh3, Neh4, and Neh5 domains are necessary for transactivation. Neh7 is necessary for binding with the RXRα.

Figure 2

Regulation of Nrf2 signaling. Nrf2 pathway is regulated at different levels: (A) transcriptional mechanism to induce a positive regulation through binding to XRE or ARE in the NFE2L2 gene promoter region. NF-κB, c-Jun, and c-Fos can regulate negatively NFE2L2 transcription. (B) NFE2L2 is also regulated in an epigenetic or post-transcriptional manner including DNA methylation, histone modification, and microRNAs. miRNAs can induce Keap1 mRNA degradation or Nrf2 mRNA inactivation/stabilization. (C) Nrf2 is also regulated at the translational level through an internal ribosomal entry site (IRES) that can initiate/inhibit Nrf2 mRNA translation. (D) Nrf2 may be also regulated by Keap1-, β-TrCP- and Hrd1-mediated Nrf2 proteasomal degradation.

Figure 3

Activation of the Nrf2 signaling pathway in kidney diseases. Several nephrotoxic stimuli, such as ROS, proteinuria, hyperglycemia, uremic toxins, or inflammation, promote Nrf2 activation in the kidney (fibroblasts, infiltrating leucocytes, tubuloepithelial, glomerular and endothelial cells). Activated Nrf2 induces the expression of phase II enzymes and inhibits the activation of intracellular pathways associated with renal injury (MAPKs, p38, JUN, ERK, JAK/STAT, NF-κB, TLRs), reducing oxidative stress, cell death, inflammation, and fibrosis.