Role of Nuclear Factor Erythroid 2-Related Factor 2 in Diabetic Nephropathy

Table 1

Beneficial effect of Nrf2 activators on experimental DN.

Nrf2 activator	DN model	Results	Ref.
Sulforaphane	T1DM mice; human renal tubular cells	Sulforaphane alleviates renal inflammation, oxidative stress, fibrosis, and dysfunction in DN mice via activation of Nrf2/ARE pathway (HO-1, SOD1, etc.); beneficial effects disappeared when Nrf2 siRNA was applied	[85]
Sulforaphane	T1DM mice; human renal mesangial cells	Sulforaphane normalizes diabetes-induced kidney oxidative damage, fibrosis, and apoptosis, which is mediated by Nrf2/ARE pathway (NQO1, rGCS, and MRP2) activation; beneficial effects disappeared in Nrf2 knockout mice	[86]
Sulforaphane	T2DM mice	Sulforaphane improves kidney oxidative damage, inflammation, and fibrosis in diabetic mice, accompanied by increasing kidney Nrf2 and its downstream gene metallothionein; beneficial effects disappeared in Nrf2 knockout mice	[89]
Sulforaphane	T1DM rats	Sulforaphane ameliorates DN through GSK3β/Fyn/Nrf2 signaling pathway (prevents nuclear export of Nrf2)	[96]
Resveratrol and rosuvastatin	T1DM mice	Resveratrol combined with rosuvastatin treatment normalizes the TGF-β1, FN, and NF-κB/p65 and restores Nrf2 in renal tissues of diabetic rats	[74]
Resveratrol	T1DM rats; rat mesangial cells	Resveratrol reduces albuminuria and mesangial matrix expansion in DN rats and attenuates mesangial cell proliferation, which is associated with upregulation of Nrf2 and glutathione S-transferases Mu	[84]
Resveratrol	T1DM rats	Resveratrol protects against DN by alleviating oxidative damage and inflammation through Nrf2/ARE pathway (SOD, CAT, etc.)	[87]
Resveratrol	Rat primary glomerular; mesangial cells	Resveratrol inhibits AGE-induced FN and TGF-β1 in glomerular; mesangial cells through Sirt1/Nrf2 signaling pathway activation	[101]
Polydatin (resveratrol analogue)	T1DM rats; rat glomerular mesangial cells	Polydatin inhibits AGE-induced FN and TGF-β1 in glomerular mesangial cells is associated with activation of Sirt1/Nrf2 pathway	[97]
Curcumin	T2DM rats	Curcumin ameliorates albuminuria, kidney pathophysiologic changes, and urinary MDA, accompanied by increasing Nrf2, HO-1, and urinary SOD	[78]
Curcumin	Rat kidney tubular epithelial cells	Curcumin protects renal tubular cells from high glucose-induced EMT through upregulating Nrf2 and HO-1; beneficial effects disappeared when Nrf2 siRNA was applied	[80]
C66 (curcumin analogue)	T1DM mice	C66 protects against DN by upregulating Nrf2 via both increasing; miR-200a and inhibiting miR-21; beneficial effects were partially; abolished in Nrf2 knockout mice	[93]
Zinc	Human renal tubular cells	Zn sensitizes Nrf2 by facilitating Akt-associated Fyn inhibition; (prevents Nrf2 nuclear export) and thus alleviates kidney oxidative; and inflammatory damage and fibrosis	[98]
Zinc	Rat kidney tubular; epithelial cells	Zinc ameliorates high glucose-mediated apoptosis in rat kidney; tubular cells through Akt/ERK/Nrf2 signaling pathway activation; (promotes Nrf2 accumulation in nuclear)	[99]
MG132	T1DM mice; human renal tubular cells	MG132 sensitizes Nrf2 by inhibiting proteasome activity and thus; attenuates hyperglycemia-induced kidney oxidative and inflammatory; damage, fibrosis, and eventual dysfunction; beneficial effects; disappeared when Nrf2 siRNA was applied	[57]
MG132	T1DM rats	Low dose of MG132 prevents diabetes-induced kidney damage by; Nrf2/ARE pathway activation	[106]
Rutin	Human renal glomerular; endothelial cells	Rutin significantly prevents hyperglycemia-induced glomerular endothelial barrier disruption by decreasing ROS through the activation of Nrf2	[71]
Berberine	T1DM mice; rat renal tubular epithelial cells	Berberine ameliorates high glucose-induced EMT and oxidative stress; by Nrf2/ARE pathway (HO-1 and NQO1) activation and TGF-β/EMT; pathway inhibition; beneficial effects disappeared when Nrf2 siRNA; was applied	[72]
Casein kinase 2 interacting protein-1	Rat glomerular mesangial cells	Casein kinase 2 interacting protein-1 downregulates ICAM-1 and FN by Nrf2/ARE pathway (SOD1 and HO-1) activation	[73]
Salvianolic acid A	T1DM mice	Salvianolic acid A protects DN via Nrf2/ARE pathway; (HO-1, NQO1, and GPx-1)	[75]
Sinomenine	Human renal glomerular; endothelial cells	Sinomenine reduces ROS level and exerts renal protective effect by; activating Nrf2 in high glucose-treated human renal glomerular; endothelial cells	[76]
Momordica charantia polysaccharides	T1DM rats	Momordica charantia polysaccharides attenuate type 1 DN in rats by upregulating Nrf2, CAT, GSH, and SOD	[77]
Digitoflavone	T1DM mice	Digitoflavone minimizes pathological changes, decreases oxidative and inflammatory damage as well as fibrosis in DN mice, which is mediated by Nrf2 pathway (GCLC and HO-1) activation; beneficial effects disappeared in Nrf2 knockout mice	[78]
Thrombomodulin domain 1	T2DM mice	Thrombomodulin domain 1 improves DN by suppressing inflammation, activating the Nrf2 pathway, and inhibiting apoptosis in the mouse kidney	[82]
Maxacalcitol	T2DM mice	Maxacalcitol alleviates DN by suppressing kidney oxidative and; inflammatory damage as well as fibrosis, which is mediated by Nrf2; pathway (GCLC and HO-1) activation	[83]
4-Phenylbutyric acid	T1DM rats	Treatment with 4-phenylbutyric acid attenuates oxidative damage in DN rats via Nrf2 facilitation	[88]
Sodium butyrate	T1DM mice	Sodium butyrate protects against DN through Nrf2 upregulation, which is mediated by suppressing HDAC function; beneficial effects disappeared in Nrf2 knockout mice	[90]
Connexin43	Primary glomerular mesangial cells; type 2 diabetic mice	Connexin43 activates Nrf2/ARE pathway by means of inhibiting c-Src activity to hinder the nuclear export of Nrf2 and then downregulates FN, ICAM-1, and TGF-β1 expression and ultimately attenuates renal fibrosis in diabetic mice	[91]
Minocycline	T1DM/T2DM mice; human/mouse podocytes	Minocycline stabilizes endogenous Nrf2 by reducing its ubiquitination and reduces markers of oxidative damage, thus alleviated DN; beneficial effects disappeared in Nrf2 knockout mice	[92]
Mycophenolate mofetil	T1DM rats	Mycophenolate mofetil attenuates DN at least in part by upregulating Nrf2 pathway (increases the nuclear accumulation of Nrf2)	[94]
Fenofibrate	T1DM mice	Fenofibrate attenuates DN via increasing FGF21 and activating; Akt/GSK-3β/Fyn/Nrf2 pathway (prevents Nrf2 nuclear export)	[95]
Hydrogen sulfide	T1DM rats; rat glomerular mesangial cells	Hydrogen sulfide alleviates DN by suppressing oxidative stress; (promotes Nrf2 accumulation in nuclear), inflammation, and; renin-angiotensin system activity, as well as by reducing mesangial; cell proliferation	[100]
Low-dose radiation	T1DM mice	Prevention of low-dose radiation against DN is associated with Akt; phosphorylation and Nrf2 upregulation	[102]
Hepatocyte growth factor	Rat mesangial cells	Hepatocyte growth factor ameliorates high glucose-induced oxidative damage in rat mesangial cells by upregulating 8-nitro-cGMP production, accompanied by nuclear accumulation of Nrf2	[103]
Telmisartan	T2DM mice	Telmisartan inhibits NAD(P)H oxidase and upregulates Nrf2 and SOD, leading to the attenuation of diabetes-induced renal damage	[104]
tert-butylhydroquinone	T1DM mice	tert-butylhydroquinone reduces renal damage through nuclear; accumulation of Nrf2 as well as its target genes in type 1 diabetic mice	[105]