NRF2 in kidney physiology and disease

Abstract

The role of NRF2 in kidney biology has received considerable interest over the past decade. NRF2 transcriptionally controls genes responsible for cellular protection against oxidative and electrophilic stress and has anti-inflammatory functions. NRF2 is expressed throughout the kidney and plays a role in salt and water handling. In disease, animal studies show that NRF2 protects against tubulointerstitial damage and reduces interstitial fibrosis and tubular atrophy, and may slow progression of polycystic kidney disease. However, the role of NRF2 in proteinuric glomerular diseases is controversial. Although the NRF2 inducer, bardoxolone methyl (CDDO-Me), increases glomerular filtration rate in humans, it has not been shown to slow disease progression in diabetic kidney disease and Alport syndrome. Furthermore, bardoxolone methyl was associated with negative effects on fluid retention, proteinuria, and blood pressure. Several animal studies replicate findings of worsened proteinuria and a more rapid progression of kidney disease, although considerable controversy exists. It is clear that further study is needed to better understand the effects of NRF2 in the kidney. This review summarizes the available data to clarify the promise and risks associated with targeting NRF2 activity in the kidney.

Keywords: bardoxolone methyl; chronic kidney disease; electrophiles; oxidative stress; proteinuria.

FIGURE 1

The KEAP1/NRF2 Pathway. KEAP1 is the endogenous inhibitor of NRF2, directing it for ubiquitination and subsequent degradation via the proteasome. However, in the presence of oxidative stress, electrophiles, or NRF2‐inducing agents, KEAP1 is modified and NRF2 is allowed to accumulate. Free NRF2 translocates to the nucleus and partners with sMAF transcription factors to upregulate gene expression. Many of these genes have antioxidant, detoxifying, or other cytoprotective properties. KEAP1, Kelch‐like associated protein 1; NRF2, nuclear factor 2 erythroid 2; sMAF, small musculo‐aponeurotic fibrosarcoma; ARE, antioxidant response element; NQO1, NAD(P)H quinone dehydrogenase 1; CAT, catalase; HMOX, heme oxygenase 1; GST, glutathione S‐transferases; GCLC, glutamate‐cysteine ligase catalytic subunit.

FIGURE 2

Overview of the effects of NRF2. Animal studies have shown that NRF2 activation, when properly timed, can mitigate AKI, AKI‐to‐CKD progression, renal fibrosis, and cystogenesis in autosomal dominant polycystic kidney disease (ADPKD). Conversely, in glomerular diseases such as human diabetic kidney disease and Alport syndrome, NRF2 has not been shown to have a clear effect to slow disease progression. Many animal studies also show deleterious effects in glomerular disease models. Furthermore, NRF2 appears to have negative effects on congestive heart failure (CHF) and fluid accumulation, blood pressure (BP), and even kidney disease and proteinuria.