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.

Chronic Inflammation in Chronic Kidney Disease Progression: Role of Nrf2

“…Nrf2 heterodimerizes with sMaf proteins K, G, and F within the nucleus, which facilitates recognition of an enhancer sequence known as an antioxidant response element that is found in the regulatory regions of more than 250 genes. 3,70,[72][73][74] The Role of Nrf2 in Regulating Inflammation Nrf2 protects kidney cells and other tissues by upregulating an array of genes and consequently attenuating the production of proinflammatory cytokines. 15 Molecules with levels that are increased by Nrf2 include catalase, superoxide dismutase, glutathione peroxidase, heme oxygenase-1, reduced nicotinamide adenine dinucleotide phosphate quinone oxidoreductase, and glutamate-cysteine ligase.…”

“…15 An equilibrium between protein synthesis and proteasomal degradation is required to maintain the intracellular concentration of Nrf2 at a low level. 74 The cytosolic inhibitor Keap1 binds to Nrf2 in the cytoplasm. 67,71,75 Under normal conditions, Keap1 targets Nrf2 for degradation by the ubiquitin-proteasome system (Supplementary Figure S1).…”

Keap1/Nrf2 Signaling Pathway

“…Therefore, investigations of the protective effects of Keap1/Nrf2 signaling that focus on specific tissues or organs are of great interest. Such studies have traditionally focused on tissues with detoxification functions such as the liver [ 6 , 7 ] but have also expanded to diverse tissues, including the kidney [ 8 , 9 ], skin [ 10 ], lung [ 11 ], colon [ 12 ], heart [ 13 ], nervous system [ 14 ], adipose tissue [ 15 ], pancreas [ 16 ] and thyroid [ 17 , 18 ], as evidenced by the respective tissue/organ-specific studies that are outlined below and comprise the majority of studies in the present Special Issue. Lastly, research on Nrf2 has expanded to encompass not only basic but also translational and clinical studies.…”

“…Besides the liver, the kidney is a major detoxification organ. Guerrero-Hue et al review the protective roles of Nrf2 in renal disease [ 8 ]. This is a field of major clinical interest but also controversy, since a large phase 3 clinical trial of bardoxolone methyl in patients with chronic kidney disease and diabetes mellitus was terminated prematurely due to an increased risk of heart failure and cardiovascular events [ 27 ].…”

“…The underlying reasons for the observed toxicity remain unclear, and further clinical trials of bardoxolone methyl for renal diseases have been authorized. These aspects are discussed in detail in the comprehensive review by Guerrero-Hue et al [ 8 ], and they are of relevance to anyone interested in clinical applications of Nrf2 activators, regardless of the indication.…”