Nrf2 Protein Serum Concentration in Human CKD Shows a Biphasic Behavior

Abstract

Oxidative stress contributes to the progression of chronic kidney disease (CKD) and CKD-related mortality. The nuclear factor erythroid 2-related factor 2 (Nrf2) is essential in the regulation of cellular redox status, and Nrf2-activating therapies are under evaluation in several chronic diseases, including CKD. It is therefore inevitable to understand how Nrf2 behaves in advancing CKD. We analyzed Nrf2 protein concentrations in patients with varying extents of CKD but without renal replacement therapy, and in healthy subjects. Compared to healthy controls, Nrf2 protein was upregulated in mild to moderate kidney function impairment (G1-3). Within the CKD population, we found a significant positive correlation between Nrf2 protein concentration and kidney function (estimated glomerular filtration rate). In severe kidney function impairment (G4,5), Nrf2 protein was reduced compared to mild to moderate kidney function impairment. We conclude that Nrf2 protein concentration in severe kidney function impairment is reduced relative to the mild to moderate kidney function impairment where increased Nrf2 protein concentrations prevail. With respect to the implementation of Nrf2 targeted therapies, it will be necessary to explore in which population of patients with CKD such therapies are able to effectively add to the endogenous Nrf2 activity.

Keywords: CKD stage; Nrf2; Nrf2 activation; chronic kidney disease; diabetes; inflammation; kidney function; oxidative stress; redox regulation; renal failure.

Figure 1

Nuclear factor erythroid 2-related factor 2 (Nrf2) protein concentrations in healthy control subjects, mild to moderate, and severe kidney function impairment. Nrf2 protein concentration in serum was determined by ELISA. The values are shown as box and whiskers (minimum to maximum). The Nrf2 protein concentration was significantly higher in patients with mild to moderate kidney function impairment compared to healthy subjects (Dunn’s post test * p < 0.05) and patients with severe kidney function impairment (Dunn’s post test ** p < 0.01).