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

Christoffer Juul-Nielsen, Jianlin Shen, Peter Stenvinkel, Alexandra Scholze

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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.

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