Nrf2-Keap1 Activation as A Potential Target of The Antioxidant Defense System in Diabetes Mellitus

Year 2024, Volume: 33 Issue: 1, 48 - 57, 31.03.2024

Shireen Adil Alı , Tuğçe Sapmaz Erçakallı , Samet Kara , Sait Polat

https://doi.org/10.17827/aktd.1435519

Abstract

Diabetes mellitus (DM) is a chronic disease characterized by hyperglycemia and complications that include micro- and macrovascular disease. Nrf2 and its endogenous inhibitor, Keap1, function as a ubiquitous, evolutionarily conserved intracellular defense mechanism to counteract oxidative stress. Sequestered by cytoplasmic Keap1 and targeted to proteasomal degradation in basal conditions, in case of oxidative stress Nrf2 detaches from Keap1 and translocate to the nucleus, where it heterodimerizes with one of the small Maf proteins. The heterodimers recognize the AREs, that are enhancer sequences present in the regulatory regions of Nrf2 target genes, essential for the recruitment of key factors for transcription. Oxidative stress is the major pathogenic factor in diabetes and is mediated by Nrf2, a master regulator of the antioxidant protection response. This response involves a network of cooperating enzymes involved in drug detoxification and metabolic elimination of prooxidants. NRF2-induced antioxidant metabolic pathways include enzymes for the production, utilization, and regeneration of reduced glutathione (GSH). Nrf2 has been shown to have a protective effect on oxidative, inflammatory, and apoptotic. Keap1/Nrf2 signaling pathway can effectively suppress intracellular ROS overproduction and protect pancreatic β-cells from oxidative stress-induced DNA damage, contributing to the suppression of T1DM development. However, inhibition of the Keap1/Nrf2 signaling pathway significantly promoted the progression of T1DM. Diabetic complications can occur in long-term diabetes due to disturbances in metabolic balance, leading microvascular and macrovascular complication. It has been suggested that NRF2-related epigenetic changes reduce the occurrence and progression of diabetic complications by inhibiting oxidative stress. Various of antioxidant such as Vitamins like A, E, C vitamins, carotenoids, and minerals like zinc, manganese, copper, iron, and selenium are essential for the activity of NRF-2 also the natural antioxidants such as curcumin and flavonoids found in vegetables, fruits, and edible herbs also play an important role in activating the Nrf2 signaling pathway. In this review, we summarize the role of oxidative stress in diabetic pathogenesis and the role of antioxidants in the regulation of NRF-2 in the treatment of diabetic mellitus.

Keywords

Diabetic Mellitus, Oxidative stress, NRF-2- Keap1, Antioxidant, Diabetic complication.

Diabetes Mellitus'ta Nrf2-Keap1 Aktivasyonu, Antioksidan Savunma Sisteminin Potansiyel Bir Hedefidir

Abstract

Diabetes mellitus (DM), hiperglisemi ile karakterize kronik bir hastalıktır ve mikro- ve makrovasküler hastalıkları içeren komplikasyonları vardır. Nrf2 ve endojen inhibitörü Keap1, oksidatif stresle mücadele etmek için yaygın, evrimsel olarak korunmuş hücresel bir savunma mekanizması olarak işlev görür. Sitoplazmik Keap1 tarafından tutulur ve bazal koşullarda proteazomal bozulmaya hedeflenir, oksidatif stres durumunda Nrf2, Keap1'den ayrılır ve çekirdeğe taşınır, burada küçük Maf proteinlerinden biri ile heterodimer oluşturur. Heterodimerler, Nrf2 hedef genlerinin düzenleyici bölgelerinde bulunan güçlendirici dizileri (ARE'ler) tanır, transkripsiyon için önemli faktörlerin rekrütasyonu için gereklidir. Oksidatif stres, diyabetin ana patojenik faktörüdür ve Nrf2 tarafından iletilir, antioksidan koruma tepkisinin ana düzenleyicisidir. Bu yanıt, ilaç detoksifikasyonu ve prooksidanların metabolik eliminasyonunda yer alan bir dizi işbirliği yapan enzimi içeren bir ağa dahil olur. NRF2 tarafından indüklenen antioksidan metabolik yollar, azalmış glutatyonun (GSH) üretimi, kullanımı ve rejenerasyonu için enzimleri içerir. Nrf2'nin oksidatif, iltihaplı ve apoptotik etkileri koruyucu olduğu gösterilmiştir. Keap1/Nrf2 sinyal yolunun pankreatik β-hücreleri oksidatif stres kaynaklı DNA hasarından koruyarak T1DM gelişimini bastırmaya katkıda bulunduğu gösterilmiştir. Bununla birlikte, Keap1/Nrf2 sinyal yolunun inhibisyonu T1DM'nin ilerlemesini önemli ölçüde teşvik etmiştir. Uzun süreli diyabet sonucu diyabetik komplikasyonlar, metabolik dengesizliklerde meydana gelebilir, mikrovasküler ve makrovasküler komplikasyonlara yol açabilir. NRF2 ile ilişkili epigenetik değişikliklerin, oksidatif stresi inhibe ederek diyabetik komplikasyonların oluşumunu ve ilerlemesini azalttığı öne sürülmüştür. Ayrıca A, E, C vitaminleri ve karotenoidler gibi vitaminler ile çinko, mangan, bakır, demir ve selenyum gibi mineraller gibi çeşitli antioksidanlar NRF-2'nin aktivitesi için esastır, ayrıca sebzelerde, meyvelerde ve yenilebilir otlarda bulunan doğal antioksidanlar da Nrf2 sinyal yolunun aktive edilmesinde önemli bir rol oynar. Bu derlemede, diyabetik patogenezde oksidatif stresin rolünü ve diabetes mellitus tedavisinde NRF-2'nin düzenlenmesinde antioksidanların rolünü özetliyoruz.

Keywords

Diabetes Mellitus, Oksidatif stres, NRF-2- Keap1, Antioksidan, Diyabetik komplikasyon.

References

• 1. Pisoschi AM, Pop A, Iordache F, Stanca L, Predoi G, Serban AI. Oxidative stress mitigation by antioxidants - An overview on their chemistry and influences on health status. Eur J Med Chem. 2021;209:112891. doi:10.1016/j.ejmech.2020.112891
• 2. Smith KA, Waypa GB, Schumacker PT. Redox signaling during hypoxia in mammalian cells. Redox Biol. 2017;13(May):228-234. doi:10.1016/j.redox.2017.05.020
• 3. Hussain T, Tan B, Yin Y, Blachier F, Tossou MCB, Rahu N. Oxidative Stress and Inflammation: What Polyphenols Can Do for Us? Oxid Med Cell Longev. 2016;2016. doi:10.1155/2016/7432797
• 4. Duracková Z. Some current insights into oxidative stress. Physiol Res. 2010;59(4):459-469. http://www.ncbi.nlm.nih.gov/pubmed/19929132
• 5. Steven S, Daiber A, Dopheide JF, Münzel T, Espinola-Klein C. Peripheral artery disease, redox signaling, oxidative stress – Basic and clinical aspects. Redox Biol. 2017;12(March):787-797. doi:10.1016/j.redox.2017.04.017
• 6. Forman HJ, Zhang H. Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nat Rev Drug Discov. 2021;20(9):689-709. doi:10.1038/s41573-021-00233-1
• 7. Ma Q. Role of Nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 2013;53(1):401-426. doi:10.1146/annurev-pharmtox-011112-140320
• 8. Pham-Huy LA, He H, Pham-Huy C. Free radicals, antioxidants in disease and health. Int J Biomed Sci. 2008;4(2):89-96.
• 9. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 2000;408(6809):239-247.
• 10. Schrader M, Fahimi HD. Peroxisomes and oxidative stress. Biochim Biophys Acta (BBA)-Molecular Cell Res. 2006;1763(12):1755-1766.
• 11. Antonenkov VD, Grunau S, Ohlmeier S, Hiltunen JK. Peroxisomes are oxidative organelles. Antioxid Redox Signal. 2010;13(4):525-537.
• 12. Konno T, Melo EP, Chambers JE, Avezov E. Intracellular sources of ROS/H2O2 in health and neurodegeneration: spotlight on endoplasmic reticulum. Cells. 2021;10(2):233.
• 13. Victor P, Sarada D, Ramkumar KM. Crosstalk between endoplasmic reticulum stress and oxidative stress: Focus on protein disulfide isomerase and endoplasmic reticulum oxidase 1. Eur J Pharmacol. 2021;892:173749.
• 14. Moussa Z, Judeh ZM, Ahmed SA. Nonenzymatic exogenous and endogenous antioxidants. Free Radic Med Biol. 2019;1:11-22.
• 15. McCord JM, Fridovich I. Superoxide dismutase: the first twenty years (1968–1988). Free Radic Biol Med. 1988;5(5-6):363-369.
• 16. Chelikani P, Fita I, Loewen PC. Diversity of structures and properties among catalases. Cell Mol Life Sci C. 2004;61:192-208.
• 17. Mirończuk-Chodakowska I, Witkowska AM, Zujko ME. Endogenous non-enzymatic antioxidants in the human body. Adv Med Sci. 2018;63(1):68-78.
• 18. Powers SK, Jackson MJ. Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production. Physiol Rev. 2008;88(4):1243-1276.
• 19. Iacobini C, Vitale M, Pesce C, Pugliese G. Diabetic Complications and Oxidative Stress : A 20-Year Voyage Back in Time and Back to the Future. Published online 2021.
• 20. Vlassara H. Recent progress in advanced glycation end products and diabetic complications. Diabetes. 1997;46(Supplement_2):S19-S25.
• 21. Babizhayev MA, Kasus-Jacobi A. State of the art clinical efficacy and safety evaluation of N-acetylcarnosine dipeptide ophthalmic prodrug. Principles for the delivery, self-bioactivation, molecular targets and interaction with a highly evolved histidyl-hydrazide structure in the treatm. Curr Clin Pharmacol. 2009;4(1):4-37.
• 22. Tilton RG. Diabetic vascular dysfunction: links to glucose‐induced reductive stress and VEGF. Microsc Res Tech. 2002;57(5):390-407.
• 23. Cosentino F, Assenza GE. Diabetes and inflammation. Herz. 2004;29(8):749.
• 24. Okon UA, Umoren IU. Comparison of antioxidant activity of insulin, Ocimum gratissimum L., and Vernonia amygdalina L. in type 1 diabetic rat model. J Integr Med. 2017;15(4):302-309.
• 25. Wang Y, Zhang Z, Sun W, et al. Sulforaphane attenuation of type 2 diabetes-induced aortic damage was associated with the upregulation of Nrf2 expression and function. Oxid Med Cell Longev. 2014;2014.
• 26. Evcimen N Das, King GL. The role of protein kinase C activation and the vascular complications of diabetes. Pharmacol Res. 2007;55(6):498-510.
• 27. C Tobon-Velasco J, Cuevas E, A Torres-Ramos M. Receptor for AGEs (RAGE) as mediator of NF-kB pathway activation in neuroinflammation and oxidative stress. CNS Neurol Disord Targets (Formerly Curr Drug Targets-CNS Neurol Disord. 2014;13(9):1615-1626.
• 28. Yamamoto M, Kensler TW, Motohashi H. The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol Rev. 2018;98(3):1169-1203.
• 29. Theodore M, Kawai Y, Yang J, et al. Multiple nuclear localization signals function in the nuclear import of the transcription factor Nrf2. J Biol Chem. 2008;283(14):8984-8994.
• 30. Nioi P, Nguyen T, Sherratt PJ, Pickett CB. The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation. Mol Cell Biol. 2005;25(24):10895-10906.
• 31. Motohashi H, Yamamoto M. Nrf2–Keap1 defines a physiologically important stress response mechanism. Trends Mol Med. 2004;10(11):549-557. doi:https://doi.org/10.1016/j.molmed.2004.09.003
• 32. Tong KI, Katoh Y, Kusunoki H, Itoh K, Tanaka T, Yamamoto M. Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Mol Cell Biol. 2006;26(8):2887-2900.
• 33. Dinkova-Kostova AT, Abramov AY. The emerging role of Nrf2 in mitochondrial function. Free Radic Biol Med. 2015;88:179-188.
• 34. Baird L, Swift S, Llères D, Dinkova-Kostova AT. Monitoring Keap1–Nrf2 interactions in single live cells. Biotechnol Adv. 2014;32(6):1133-1144.
• 35. Baird L, Yamamoto M. The molecular mechanisms regulating the KEAP1-NRF2 pathway. Mol Cell Biol. 2020;40(13):e00099-20.
• 36. Hirotsu Y, Katsuoka F, Funayama R, et al. Nrf2–MafG heterodimers contribute globally to antioxidant and metabolic networks. Nucleic Acids Res. 2012;40(20):10228-10239.
• 37. Tonelli C, Chio IIC, Tuveson DA. Transcriptional regulation by Nrf2. Antioxid Redox Signal. 2018;29(17):1727-1745.
• 38. Oh YS, Jun HS. Effects of glucagon-like peptide-1 on oxidative stress and Nrf2 signaling. Int J Mol Sci. 2017;19(1):26.
• 39. Yavari A, Javadi M, Mirmiran P, Bahadoran Z. Exercise-induced oxidative stress and dietary antioxidants. Asian J Sports Med. 2015;6(1).
• 40. Taguchi K, Yamamoto M. The KEAP1–NRF2 system in cancer. Front Oncol. 2017;7:85.
• 41. Wang X he, Cui X xu, Sun X qi, et al. High fat diet-induced hepatic 18-carbon fatty acids accumulation up-regulates CYP2A5/CYP2A6 via NF-E2-related factor 2. Front Pharmacol. 2017;8:233.
• 42. Vomund S, Schäfer A, Parnham MJ, Brüne B, Von Knethen A. Nrf2, the master regulator of anti-oxidative responses. Int J Mol Sci. 2017;18(12):2772.
• 43. He F, Antonucci L, Karin M. NRF2 as a regulator of cell metabolism and inflammation in cancer. Carcinogenesis. 2020;41(4):405-416.
• 44. Younis NS, Abduldaium MS, Mohamed ME. Protective effect of geraniol on oxidative, inflammatory and apoptotic alterations in isoproterenol-induced cardiotoxicity: Role of the Keap1/Nrf2/HO-1 and PI3K/Akt/mTOR pathways. Antioxidants. 2020;9(10):977.
• 45. Guerrero-Hue M, Rayego-Mateos S, Vázquez-Carballo C, et al. Protective role of Nrf2 in renal disease. Antioxidants. 2020;10(1):39.
• 46. De Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med. 2013;369(26):2492-2503.
• 47. Lou Y, Kong M, Li L, et al. Inhibition of the Keap1/Nrf2 signaling pathway significantly promotes the progression of type 1 diabetes mellitus. Oxid Med Cell Longev. 2021;2021.
• 48. Fu J, Hou Y, Xue P, et al. Nrf2 in Type 2 diabetes and diabetic complications: Yin and Yang. Curr Opin Toxicol. 2016;1(August):9-19. doi:10.1016/j.cotox.2016.08.001
• 49. Adams TD, Arterburn DE, Nathan DM, Eckel RH. Clinical outcomes of metabolic surgery: microvascular and macrovascular complications. Diabetes Care. 2016;39(6):912-923.
• 50. Yang J, Wu R, Li W, et al. The triterpenoid corosolic acid blocks transformation and epigenetically reactivates Nrf2 in TRAMP‐C1 prostate cells. Mol Carcinog. 2018;57(4):512-521.
• 51. Sun L, Li X, Li G, Dai B, Tan W. Actinidia chinensis planch. Improves the indices of antioxidant and anti-inflammation status of type 2 diabetes mellitus by activating Keap1 and Nrf2 via the upregulation of MicroRNA-424. Oxid Med Cell Longev. 2017;2017.
• 52. Zhao Q, Zhang F, Yu Z, et al. HDAC3 inhibition prevents blood-brain barrier permeability through Nrf2 activation in type 2 diabetes male mice. J Neuroinflammation. 2019;16(1):1-15.
• 53. Wei J, Zhang Y, Luo Y, et al. Aldose reductase regulates miR-200a-3p/141-3p to coordinate Keap1–Nrf2, Tgfβ1/2, and Zeb1/2 signaling in renal mesangial cells and the renal cortex of diabetic mice. Free Radic Biol Med. 2014;67:91-102.
• 54. Song J, Zhang H, Sun Y, et al. Omentin-1 protects renal function of mice with type 2 diabetic nephropathy via regulating miR-27a-Nrf2/Keap1 axis. Biomed Pharmacother. 2018;107:440-446.
• 55. Zhang J, Cai W, Fan Z, et al. MicroRNA-24 inhibits the oxidative stress induced by vascular injury by activating the Nrf2/Ho-1 signaling pathway. Atherosclerosis. 2019;290:9-18.
• 56. Baumel-Alterzon S, Katz LS, Brill G, Garcia-Ocaña A, Scott DK. Nrf2: the master and captain of beta cell fate. Trends Endocrinol Metab. 2021;32(1):7-19.
• 57. Hegazy AM, El-Sayed EM, Ibrahim KS, Abdel-Azeem AS. Dietary antioxidant for disease prevention corroborated by the Nrf2 pathway. J Complement Integr Med. 2019;16(3):20180161.
• 58. Galano A. Relative antioxidant efficiency of a large series of carotenoids in terms of one electron transfer reactions. J Phys Chem B. 2007;111(44):12898-12908.
• 59. Wang G, Xiu P, Li F, Xin C, Li K. Vitamin A supplementation alleviates extrahepatic cholestasis liver injury through Nrf2 activation. Oxid Med Cell Longev. 2014;2014.
• 60. Quoc QL, Bich TCT, Kim S, Park H, Shin YS. Administration of vitamin E attenuates airway inflammation through restoration of Nrf2 in a mouse model of asthma. J Cell Mol Med. 2021;25(14):6721.
• 61. Ma Q. Transcriptional responses to oxidative stress: pathological and toxicological implications. Pharmacol Ther. 2010;125(3):376-393.
• 62. Patel SS, Acharya A, Ray RS, Agrawal R, Raghuwanshi R, Jain P. Cellular and molecular mechanisms of curcumin in prevention and treatment of disease. Crit Rev Food Sci Nutr. 2020;60(6):887-939.
• 63. Kim S, Lee HG, Park SA, et al. Keap1 cysteine 288 as a potential target for diallyl trisulfide-induced Nrf2 activation. PLoS One. 2014;9(1):e85984.
• 64. Dinkova-Kostova AT, Fahey JW, Kostov R V, Kensler TW. KEAP1 and done? Targeting the NRF2 pathway with sulforaphane. Trends food Sci Technol. 2017;69:257-269.
• 65. Pérez-Rubio KG, González-Ortiz M, Martínez-Abundis E, Robles-Cervantes JA, Espinel-Bermúdez MC. Effect of berberine administration on metabolic syndrome, insulin sensitivity, and insulin secretion. Metab Syndr Relat Disord. 2013;11(5):366-369.
• 66. Szkudelski T, Szkudelska K. Anti‐diabetic effects of resveratrol. Ann N Y Acad Sci. 2011;1215(1):34-39.
• 67. Zhang X, Zhao Y, Chu Q, Wang ZY, Li H, Chi ZH. Zinc modulates high glucose-induced apoptosis by suppressing oxidative stress in renal tubular epithelial cells. Biol Trace Elem Res. 2014;158:259-267.
• 68. Sahin K, Tuzcu M, Orhan C, et al. The effects of chromium picolinate and chromium histidinate administration on NF-κB and Nrf2/HO-1 pathway in the brain of diabetic rats. Biol Trace Elem Res. 2012;150:291-296.
• 69. Ramprasath T, Kumar PH, Puhari SSM, Murugan PS, Vasudevan V, Selvam GS. L-Arginine ameliorates cardiac left ventricular oxidative stress by upregulating eNOS and Nrf2 target genes in alloxan-induced hyperglycemic rats. Biochem Biophys Res Commun. 2012;428(3):389-394.