Table 1.

Function of Nrf2 in the kidney. The following is a list of major studies that have demonstrated the function of Nrf2 in the kidney using animal models. (KO, knockout; CKO, conditional knockout; KD, knockdown; ds-DNA, double- stranded DNA; AGE, advanced glycation end product; CDDO, 2-cyano-3,12-dioxolane-1,9-dien-28-oic acid; BUN, blood urea nitrogen; AST, aspartate transaminase; IRI, ischemia–reperfusion-injury).

Disease Model	Intervension	Results of the Study	Ref.
Aging	Nrf2-KO	Increased mortality and worsened renal function were observed in female mice, with lupus nephritis-like findings accompanied by increased spleen weight and increased ds DNA.	[55,73]
Lupus nephritis	Nrf2-KO	Nrf2-KO mice showed improved renal function and increased survival rate and reduced immune complex deposition in renal tissue	[74]
	Nrf2-KO	Nrf2-KO mice showed decreased survival, increased spleen weight, increased oxidative stress, and aggravated fibrosis of renal tissue.	[67]
DKD (STZ)	Nrf2-KO	Nrf2-KO mice showed a similar increase in blood glucose after STZ administration, but decreased creatinine clearance and urinary albumin excretion, worsened renal pathology, and increased AGE, oxidative stress, and fibrosis markers, which were ameliorated by NRF2 activator administration.	[64,71,75]
Bilateral IRI	Nrf2-KO	Nrf2-KO mice showed elevated creatinine, worsened histology, and marked elevation of cytokines, but prior administration of N-acetylcysteine suppressed the creatinine elevation.	[65]
	CDDO-Imidazole/Bardoxolone methyl	In the CDDO-Im preadministration group, life expectancy, renal function, and renal tissue damage were improved and acute phase inflammatory cytokines were reduced.	[76,77]
Unilateral IRI	Nrf2-KO/Keap1-KD/Keap1-CKO	Nrf2-KO mice showed exacerbation of tubular damage and oxidative stress, while Keap1-KD and Keap1-CKO suppressed creatinine elevation and increased antioxidant markers.	[66]
Sepsis model	LysM-Keap1-KO/ LysM-Nrf2-KO	LysM-Keap1-KO mice showed improved survival and decreased BUN, AST, and inflammatory cytokines, while LysM-Nrf2-KO mice showed worsening of these parameters.	[78]
Cisplatin nephropathy	Nrf2-KO/ CDDO-Im	Nrf2-KO mice showed increased mortality, elevated creatinine, and worsened renal tissue damage, while CDDO-Im administration improved renal tissue.	[65,79,80]
NEP25-induced podocyte injury	Keap1-KD	Improved renal tissue, fibrosis markers, and podocyte damage in Keap1-KD mice.	[81]
Rhabdomyolysis (myoglobin) nephropathy	-	The expression of downstream genes of Nrf2 was increased in rhabdomyolysis model induced by glycerol administration; chlormethiazole alleviated these changes.	[82]
5/6 nephrectomy	-	In the 5/6 nephrectomy group, there was a decrease in Nrf2 expression and an increase in Keap1 expression.	[83]
Adriamycin, Angiotensin II-induced proteinuria	Keap1-KD	Keap1-KD mice showed increased albuminuria in adriamycin nephropathy, the angiotensin II model, and in the protein overload model.	[84]
Cynomolgus monkeys	bardoxolone methyl	Administration of bardoxolone methyl increased creatinine clearance and urinary albumin; no abnormalities in blood tests or renal tissue were noted after 1 year of treatment. The increase in urinary albumin may be due to decreased megalin expression in the tubules.	[85]