Systematic review of the nuclear factor erythroid 2-related factor 2 (NRF2) system in human chronic kidney disease: alterations, interventions and relation to morbidity

Abstract

Background NRF2 and its effectors NAD(P)H:quinoneoxidoreductase 1 (NQO1) and heme oxygenase 1 (HO-1) are of interest in kidney disease. We therefore reviewed studies about their status in patients with chronic kidney disease (CKD). Methods We undertook systematic searches of PubMed and EMBASE databases. Alterations of NRF2, NQO1 and HO-1 in CKD, their responses to interventions and their relation to clinically relevant parameters were reported. Results We identified 1373 articles, of which 32 studies met the inclusion criteria. NRF2 levels were decreased in the majority of analyses of CKD patients. Half of the analyses showed a similar or increased NQO1 level vs. control, whereas NQO1 was decreased in half of the analyses. Most of the studies reported either an increased or similar HO-1 level in CKD patients compared to controls. For patients with CKD stages 1-4, studies reported positive correlations to markers of kidney disease severity. Also, positive associations of NQO1/HO-1 levels to inflammation and comorbidities were reported. One third of the studies showed discordant changes between gene expression and protein level of NRF2 system components. Two thirds of intervention studies (50% dietary, such as using resistant starch) reported an increase of NRF2, NQO1, or HO-1. Conclusions In patients with CKD, NRF2 expression was downregulated, while NQO1 and HO-1 showed varying alterations related to inflammation, comorbidities, and severity of kidney damage. Interventions that increased NRF2 system components were described, but their effectiveness and clinical relevance require further clinical studies of high quality. Research on gene expression together with protein analyses is indispensable to understand NRF2 system alterations in CKD.

Chronic Inflammation in Chronic Kidney Disease Progression: Role of Nrf2

“…[88][89][90][91] A recent systematic review of 32 studies concludes that whereas Nrf2 expression was consistently downregulated in CKD, NQO1, and HO-1 showed varying alterations related to inflammation, comorbidities, and severity of kidney damage. 92 Jiang et al 69 showed that kidney biopsy specimens from patients with DKD demonstrated high levels of glucose-induced ROS in mesangial cells as well as activation of Nrf2 and downstream genes. By immunohistochemistry, it was demonstrated that whereas Nrf2 was expressed at low levels in normal glomeruli, it was up-regulated in glomeruli from patients with DKD.…”

Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls

“…At indoxyl-sulfate concentrations between 1 mg/L and 11 mg/L in patients with CKD3 and 4, indoxyl sulfate correlated positively with Nrf2 gene expression in peripheral blood polymorphonuclear cells (PBMCs) [ 121 ]. In light of a mainly decreased Nrf2 gene expression in advanced CKD [ 122 ], a bi-phasic, concentration-dependent effect of indoxyl sulfate in human CKD seems plausible, with Nrf2 activation in the lower concentration range and Nrf2 repression at high concentrations.…”

“…Herein, in patients with CKD3/4, higher NF-κB gene expression was associated with higher Nrf2 gene expression, likely reflecting NF-κB-driven pro-inflammatory responses and subsequent Nrf2 activation. On the other hand, in the patient group with CKD5 and hemodialysis therapy, the decrease in Nrf2, which has frequently been observed in advanced CKD [ 122 ], was present. In this group, decreased Nrf2 gene expression was associated with significantly increased NF-κB, finally amounting to a doubling of NF-κB gene expression [ 131 ] that may reflect a lack of suppressive Nrf2 action on NF-κB.…”

Involvement of Inflammasome Components in Kidney Disease

“…As in other areas of complex regulations in kidney disease, the combined investigation of a set of meaningful molecular parameters is inevitable. Thorough analyses of gene expression, protein characteristics, and protein activity together enable a better understanding of molecular networks [ 128 ]. Ideally, in investigations of inflammasomes, this comprises the gene expression and protein amount of inflammasome-related components, post-translational modifications of the inflammasome sensory components, inflammasome assembly and proteolytic activity, and production of mature interleukins [ 11 ].…”