Filtering through the role of NRF2 in kidney disease

  • Cody J. Schmidlin
  • Matthew B. Dodson
  • Donna D. ZhangEmail author


Kidney disease affects ~ 10% of the population worldwide, resulting in millions of deaths each year. Mechanistically, oxidative stress is a major driver of various kidney diseases, and promotes the progression from acute to chronic injury, as well as renal cancer development. NRF2, the master regulator of redox balance, has been shown to protect against kidney disease through its negation of reactive oxygen species (ROS). However, many kidney diseases exhibit high levels of ROS as a result of decreased NRF2 protein levels and transcriptional activity. Many studies have tested the strategy of using NRF2 inducing compounds to alleviate ROS to prevent or slow down the progression of kidney diseases. Oppositely, in specific subsets of renal cancer, NRF2 is constitutively activated and contributes to tumor burden and overall poor prognosis; therefore, there has been a recent interest in studies investigating the benefits of NRF2 inhibition. In this review, we summarize recent literature investigating the role of NRF2 and oxidative stress in various kidney diseases, and how pharmacological modification of NRF2 signaling could play a protective role.


NRF2 KEAP1 Oxidative stress Kidney disease Renal cell carcinoma Hypertension 



The lab of Dr. Zhang is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (Grant No. DK109555 [D.D.Z.]), and the National Institute of Environmental Health Sciences (Grant Nos. ES026845 [D.D.Z.], ES004940 [D.D.Z.], ES006694 [under center]).

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest to declare.


  1. Aleksunes LM, Goedken MJ, Rockwell CE, Thomale J, Manautou JE, Klaassen CD (2010) Transcriptional regulation of renal cytoprotective genes by Nrf2 and its potential use as a therapeutic target to mitigate cisplatin-induced nephrotoxicity. J Pharmacol Exp Ther 335(1):2–12Google Scholar
  2. Aminzadeh MA, Reisman SA, Vaziri ND, Khazaeli M, Yuan J, Meyer CJ (2014) The synthetic triterpenoid RTA dh404 (CDDO-dhTFEA) restores Nrf2 activity and attenuates oxidative stress, inflammation, and fibrosis in rats with chronic kidney disease. Xenobiotica 44(6):570–578Google Scholar
  3. Anders MW (1980) Metabolism of drugs by the kidney. Kidney Int 18(5):636–647Google Scholar
  4. Andries A, Daenen K, Jouret F, Bammens B, Mekahli D, Van Schepdael A (2018) Oxidative stress in autosomal dominant polycystic kidney disease: player and/or early predictor for disease progression? Pediatr Nephrol 34(6):993–1008Google Scholar
  5. Atilano-Roque A, Wen X, Aleksunes LM, Joy MS (2016) Nrf2 activators as potential modulators of injury in human kidney cells. Toxicol Rep 3:153–159Google Scholar
  6. Basile DP, Bonventre JV, Mehta R, Nangaku M, Unwin R, Rosner MH, Kellum JA, Ronco C, A. X. W. Group (2016) Progression after AKI: understanding maladaptive repair processes to predict and identify therapeutic treatments. J Am Soc Nephrol 27(3):687–697Google Scholar
  7. Bhattacharyya S, Zhou H, Seiner DR, Gates KS (2010) Inactivation of protein tyrosine phosphatases by oltipraz and other cancer chemopreventive 1,2-dithiole-3-thiones. Bioorg Med Chem 18(16):5945–5949Google Scholar
  8. Bolati D, Shimizu H, Yisireyili M, Nishijima F, Niwa T (2013) Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-kappaB. BMC Nephrol 14:56Google Scholar
  9. Bollong MJ, Yun H, Sherwood L, Woods AK, Lairson LL, Schultz PG (2015) A small molecule inhibits deregulated NRF2 transcriptional activity in cancer. ACS Chem Biol 10(10):2193–2198Google Scholar
  10. Bomprezzi R (2015) Dimethyl fumarate in the treatment of relapsing-remitting multiple sclerosis: an overview. Ther Adv Neurol Disord 8(1):20–30Google Scholar
  11. Budisavljevic MN, Hodge L, Barber K, Fulmer JR, Durazo-Arvizu RA, Self SE, Kuhlmann M, Raymond JR, Greene EL (2003) Oxidative stress in the pathogenesis of experimental mesangial proliferative glomerulonephritis. Am J Physiol Renal Physiol 285(6):F1138–F1148Google Scholar
  12. Cao Z, Yu W, Li W, Cheng F, Rao T, Yao X, Zhang X, Larre S (2015) Oxidative damage and mitochondrial injuries are induced by various irrigation pressures in rabbit models of mild and severe hydronephrosis. PLoS ONE 10(6):e0127143Google Scholar
  13. Chen DQ, Cao G, Chen H, Argyopoulos CP, Yu H, Su W, Chen L, Samuels DC, Zhuang S, Bayliss GP, Zhao S, Yu XY, Vaziri ND, Wang M, Liu D, Mao JR, Ma SX, Zhao J, Zhang Y, Shang YQ, Kang H, Ye F, Cheng XH, Li XR, Zhang L, Meng MX, Guo Y, Zhao YY (2019) Identification of serum metabolites associating with chronic kidney disease progression and anti-fibrotic effect of 5-methoxytryptophan. Nat Commun 10(1):1476Google Scholar
  14. Chin MP, Bakris GL, Block GA, Chertow GM, Goldsberry A, Inker LA, Heerspink HJL, O’Grady M, Pergola PE, Wanner C, Warnock DG, Meyer CJ (2018) Bardoxolone methyl improves kidney function in patients with chronic kidney disease stage 4 and type 2 diabetes: post hoc analyses from bardoxolone methyl evaluation in patients with chronic kidney disease and type 2 diabetes study. Am J Nephrol 47(1):40–47Google Scholar
  15. Dodson M, de la Vega MR, Cholanians AB, Schmidlin CJ, Chapman E, Zhang DD (2019) Modulating NRF2 in disease: timing is everything. Annu Rev Pharmacol Toxicol 59:555–575Google Scholar
  16. Guerrero-Hue M, Farre-Alins V, Palomino-Antolin A, Parada E, Rubio-Navarro A, Egido J, Egea J, Moreno JA (2017) Targeting Nrf2 in protection against renal disease. Curr Med Chem 24(33):3583–3605Google Scholar
  17. Harder B, Tian W, La Clair JJ, Tan AC, Ooi A, Chapman E, Zhang DD (2017) Brusatol overcomes chemoresistance through inhibition of protein translation. Mol Carcinog 56(5):1493–1500Google Scholar
  18. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13(1):76–86Google Scholar
  19. Jiang T, Huang Z, Lin Y, Zhang Z, Fang D, Zhang DD (2010) The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy. Diabetes 59(4):850–860Google Scholar
  20. Kang SJ, You A, Kwak MK (2011) Suppression of Nrf2 signaling by angiotensin II in murine renal epithelial cells. Arch Pharm Res 34(5):829–836Google Scholar
  21. Kitamura H, Motohashi H (2018) NRF2 addiction in cancer cells. Cancer Sci 109(4):900–911Google Scholar
  22. Liu M, Grigoryev DN, Crow MT, Haas M, Yamamoto M, Reddy SP, Rabb H (2009) Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice. Kidney Int 76(3):277–285Google Scholar
  23. Moradi H, Vaziri ND (2016) Effect of resveratrol on progression of polycystic kidney disease: a case of cautious optimism. Nephrol Dial Transplant 31(11):1755–1758Google Scholar
  24. Nezu M, Souma T, Yu L, Sekine H, Takahashi N, Wei AZ, Ito S, Fukamizu A, Zsengeller ZK, Nakamura T, Hozawa A, Karumanchi SA, Suzuki N, Yamamoto M (2017a) Nrf2 inactivation enhances placental angiogenesis in a preeclampsia mouse model and improves maternal and fetal outcomes. Sci Signal 10(479):eaam5711. Google Scholar
  25. Nezu M, Suzuki N, Yamamoto M (2017b) Targeting the KEAP1-NRF2 system to prevent kidney disease progression. Am J Nephrol 45(6):473–483Google Scholar
  26. Noel S, Martina MN, Bandapalle S, Racusen LC, Potteti HR, Hamad AR, Reddy SP, Rabb H (2015) T lymphocyte-specific activation of Nrf2 protects from AKI. J Am Soc Nephrol 26(12):2989–3000Google Scholar
  27. Noel S, Arend LJ, Bandapalle S, Reddy SP, Rabb H (2016) Kidney epithelium specific deletion of kelch-like ECH-associated protein 1 (Keap1) causes hydronephrosis in mice. BMC Nephrol 17(1):110Google Scholar
  28. Oey O, Rao P, Luciuk M, Mannix C, Rogers NM, Sagar P, Wong A, Rangan G (2018) Effect of dimethyl fumarate on renal disease progression in a genetic ortholog of nephronophthisis. Exp Biol Med (Maywood) 243(5):428–436Google Scholar
  29. Okamura DM, Pennathur S (2015) The balance of powers: redox regulation of fibrogenic pathways in kidney injury. Redox Biol 6:495–504Google Scholar
  30. Ooi A, Wong JC, Petillo D, Roossien D, Perrier-Trudova V, Whitten D, Min BW, Tan MH, Zhang Z, Yang XJ, Zhou M, Gardie B, Molinie V, Richard S, Tan PH, Teh BT, Furge KA (2011) An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20(4):511–523Google Scholar
  31. Ooi A, Dykema K, Ansari A, Petillo D, Snider J, Kahnoski R, Anema J, Craig D, Carpten J, Teh BT, Furge KA (2013) CUL3 and NRF2 mutations confer an NRF2 activation phenotype in a sporadic form of papillary renal cell carcinoma. Cancer Res 73(7):2044–2051Google Scholar
  32. Poss KD, Tonegawa S (1997) Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci USA 94(20):10919–10924Google Scholar
  33. Rahman M, Shad F, Smith MC (2012) Acute kidney injury: a guide to diagnosis and management. Am Fam Physician 86(7):631–639Google Scholar
  34. Ren D, Villeneuve NF, Jiang T, Wu T, Lau A, Toppin HA, Zhang DD (2011) Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc Natl Acad Sci USA 108(4):1433–1438Google Scholar
  35. Rojo de la Vega M, Chapman E, Zhang DD (2018) NRF2 and the hallmarks of cancer. Cancer Cell 34(1):21–43Google Scholar
  36. Ruiz S, Pergola PE, Zager RA, Vaziri ND (2013) Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int 83(6):1029–1041Google Scholar
  37. Saldanha JF, Leal VO, Rizzetto F, Grimmer GH, Ribeiro-Alves M, Daleprane JB, Carraro-Eduardo JC, Mafra D (2016) Effects of resveratrol supplementation in Nrf2 and NF-kappaB expressions in nondialyzed chronic kidney disease patients: a randomized, double-blind, placebo-controlled, crossover clinical trial. J Ren Nutr 26(6):401–406Google Scholar
  38. Sato Y, Yoshizato T, Shiraishi Y, Maekawa S, Okuno Y, Kamura T, Shimamura T, Sato-Otsubo A, Nagae G, Suzuki H, Nagata Y, Yoshida K, Kon A, Suzuki Y, Chiba K, Tanaka H, Niida A, Fujimoto A, Tsunoda T, Morikawa T, Maeda D, Kume H, Sugano S, Fukayama M, Aburatani H, Sanada M, Miyano S, Homma Y, Ogawa S (2013) Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet 45(8):860–867Google Scholar
  39. Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr Biol 24(10):R453–R462Google Scholar
  40. Schmidlin CJ, Dodson MB, Madhavan L, Zhang DD (2019) Redox regulation by NRF2 in aging and disease. Free Radic Biol Med 134:702–707. Google Scholar
  41. Sedeek M, Callera G, Montezano A, Gutsol A, Heitz F, Szyndralewiez C, Page P, Kennedy CR, Burns KD, Touyz RM, Hebert RL (2010) Critical role of Nox4-based NADPH oxidase in glucose-induced oxidative stress in the kidney: implications in type 2 diabetic nephropathy. Am J Physiol Renal Physiol 299(6):F1348–F1358Google Scholar
  42. Shelton LM, Park BK, Copple IM (2013) Role of Nrf2 in protection against acute kidney injury. Kidney Int 84(6):1090–1095Google Scholar
  43. Siddarth M, Chawla D, Raizada A, Wadhwa N, Banerjee BD, Sikka M (2018) Lead-induced DNA damage and cell apoptosis in human renal proximal tubular epithelial cell: attenuation via N-acetyl cysteine and tannic acid. J Biochem Mol Toxicol 32(3):e22038Google Scholar
  44. Sowers JR (2002) Hypertension, angiotensin II, and oxidative stress. N Engl J Med 346(25):1999–2001Google Scholar
  45. Su Q, Huo CJ, Li HB, Liu KL, Li X, Yang Q, Song XA, Chen WS, Cui W, Zhu GQ, Shi XL, Liu JJ, Kang YM (2017) Renin-angiotensin system acting on reactive oxygen species in paraventricular nucleus induces sympathetic activation via AT1R/PKCgamma/Rac1 pathway in salt-induced hypertension. Sci Rep 7:43107Google Scholar
  46. Suzuki T, Seki S, Hiramoto K, Naganuma E, Kobayashi EH, Yamaoka A, Baird L, Takahashi N, Sato H, Yamamoto M (2017) Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus. Nat Commun 8:14577Google Scholar
  47. Tao S, Wang S, Moghaddam SJ, Ooi A, Chapman E, Wong PK, Zhang DD (2014) Oncogenic KRAS confers chemoresistance by upregulating NRF2. Cancer Res 74(24):7430–7441Google Scholar
  48. Tao S, Rojo de la Vega M, Chapman E, Ooi A, Zhang DD (2018) The effects of NRF2 modulation on the initiation and progression of chemically and genetically induced lung cancer. Mol Carcinog 57(2):182–192Google Scholar
  49. Tapia E, Soto V, Ortiz-Vega KM, Zarco-Marquez G, Molina-Jijon E, Cristobal-Garcia M, Santamaria J, Garcia-Nino WR, Correa F, Zazueta C, Pedraza-Chaverri J (2012) Curcumin induces Nrf2 nuclear translocation and prevents glomerular hypertension, hyperfiltration, oxidant stress, and the decrease in antioxidant enzymes in 5/6 nephrectomized rats. Oxid Med Cell Longev 2012:269039Google Scholar
  50. Thangapandiyan S, Ramesh M, Miltonprabu S, Hema T, Jothi GB, Nandhini V (2019) Sulforaphane potentially attenuates arsenic-induced nephrotoxicity via the PI3K/Akt/Nrf2 pathway in albino Wistar rats. Environ Sci Pollut Res Int 26(12):12247–12263Google Scholar
  51. Tong KI, Kobayashi A, Katsuoka F, Yamamoto M (2006) Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. Biol Chem 387(10–11):1311–1320Google Scholar
  52. Touyz RM (2004) Reactive oxygen species and angiotensin II signaling in vascular cells—implications in cardiovascular disease. Braz J Med Biol Res 37(8):1263–1273Google Scholar
  53. Trpkov K, Hes O, Agaimy A, Bonert M, Martinek P, Magi-Galluzzi C, Kristiansen G, Luders C, Nesi G, Comperat E, Sibony M, Berney DM, Mehra R, Brimo F, Hartmann A, Husain A, Frizzell N, Hills K, Maclean F, Srinivasan B, Gill AJ (2016) Fumarate hydratase-deficient renal cell carcinoma is strongly correlated with fumarate hydratase mutation and hereditary leiomyomatosis and renal cell carcinoma syndrome. Am J Surg Pathol 40(7):865–875Google Scholar
  54. Wang XJ, Sun Z, Villeneuve NF, Zhang S, Zhao F, Li Y, Chen W, Yi X, Zheng W, Wondrak GT, Wong PK, Zhang DD (2008) Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis 29(6):1235–1243Google Scholar
  55. Wardyn JD, Ponsford AH, Sanderson CM (2015) Dissecting molecular cross-talk between Nrf2 and NF-kappaB response pathways. Biochem Soc Trans 43(4):621–626Google Scholar
  56. Wu M, Gu J, Mei S, Xu D, Jing Y, Yao Q, Chen M, Yang M, Chen S, Yang B, Qi N, Hu H, Wuthrich RP, Mei C (2016) Resveratrol delays polycystic kidney disease progression through attenuation of nuclear factor kappaB-induced inflammation. Nephrol Dial Transplant 31(11):1826–1834Google Scholar
  57. Yang SM, Ka SM, Wu HL, Yeh YC, Kuo CH, Hua KF, Shi GY, Hung YJ, Hsiao FC, Yang SS, Shieh YS, Lin SH, Wei CW, Lee JS, Yang CY, Chen A (2014) Thrombomodulin domain 1 ameliorates diabetic nephropathy in mice via anti-NF-kappaB/NLRP3 inflammasome-mediated inflammation, enhancement of NRF2 antioxidant activity and inhibition of apoptosis. Diabetologia 57(2):424–434Google Scholar
  58. Ye T, Zhen J, Du Y, Zhou JK, Peng A, Vaziri ND, Mohan C, Xu Y, Zhou XJ (2015) Green tea polyphenol (-)-epigallocatechin-3-gallate restores Nrf2 activity and ameliorates crescentic glomerulonephritis. PLoS ONE 10(3):e0119543Google Scholar
  59. Yim HE, Yoo KH (2008) Renin-angiotensin system—considerations for hypertension and kidney. Electrolyte Blood Press 6(1):42–50Google Scholar
  60. Zhang DD (2013) Bardoxolone brings Nrf2-based therapies to light. Antioxid Redox Signal 19(5):517–518Google Scholar
  61. Zhang DD, Hannink M (2003) Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol 23(22):8137–8151Google Scholar
  62. Zhang J, Wang X, Vikash V, Ye Q, Wu D, Liu Y, Dong W (2016) ROS and ROS-mediated cellular signaling. Oxid Med Cell Longev 2016:4350965Google Scholar
  63. Zheng H, Whitman SA, Wu W, Wondrak GT, Wong PK, Fang D, Zhang DD (2011) Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy. Diabetes 60(11):3055–3066Google Scholar

Copyright information

© The Pharmaceutical Society of Korea 2019

Authors and Affiliations

  • Cody J. Schmidlin
    • 1
  • Matthew B. Dodson
    • 1
  • Donna D. Zhang
    • 1
    • 2
    Email author
  1. 1.Department of Pharmacology and ToxicologyUniversity of ArizonaTucsonUSA
  2. 2.University of Arizona Cancer Center, University of ArizonaTucsonUSA

Personalised recommendations