Table 1.

Factors and mechanisms relevant for endogenous Nrf2 activation in human CKD.

Factor	Possible Mechanism	Observed Effects in Patients with CKD	Reference for the Patient Data
Oxidative stress	Oxidants and thiol-reactive electrophiles modify Keap1 → increase in Nrf2 translocation to the nucleus → effect on transcription of Nrf2 targets	DKD: oxidative damage of renal glomeruli,	[54]
		Nrf2 protein ↑	[116]
		NQO1 protein ↑
		LN: oxidative damage of renal glomeruli,
		Nrf2 protein ↑
		NQO1 protein ↑
		CKD5-HD: synovial tissue	[117]
		MDA ↑
		HO-1 protein ↑
Uremic toxins Indoxyl sulfate	(a) induction of ROS → effect on transcription of Nrf2 targets as above (b) activation of AhR → induction of Nrf2 gene transcription	CKD3/4:PBMCs, positive correlation between plasma indoxyl sulfate (1–11 mg/L) and Nrf2 gene expression	[121]
Methylglyoxal	Keap1 cross-linking → Keap1 dimers → Nrf2 accumulation and Nrf2-target induction	T2D with and without DKD: Lymphocytes, HO-1 protein ↑ Plasma, NQO1 protein ↑ Renal cells, Nrf2, NQO1, HO-1 protein ↑	[125]
			[126]
			[37,54,127,128]
NF-κB	NF-κB binding sites in Nrf2 gene → Nrf2 induction	CKD3/4: PBMCs, positive correlation between NF-κB and Nrf2 gene expression ↑	[131]

Abbreviations: Keap1—Kelch-like ECH-associated protein 1; ROS—reactive oxygen species; NF-κB—nuclear factor kappa B; Nrf2—Nuclear factor erythroid 2-related factor 2; AhR—arylhydrocarbon receptor; DKD—diabetic kidney disease; NQO1—NAD(P)H:quinoneoxidoreductase 1; LN—Lupus nephritis; CKD—chronic kidney disease; MDA—malondialdehyde; HO-1—heme oxygenase 1; PBMC—peripheral blood mononuclear cell; T2D—Diabetes mellitus type 2; →—leading to, ↑—increased.