open access

Ahead of print
Research paper
Published online: 2021-04-12
Get Citation

The relationship between Nrf2/Keap1 system and endoplasmic reticulum stress and inflammatory markers in peripheral blood mononuclear cells of type 2 diabetic subjects

Farshad Niazpour, Hosein Hoseini, ShadiSadat Seyyedebrahimi, Ensieh Nasli Esfahani, Reza Meshkani
DOI: 10.5603/DK.a2021.0032

open access

Ahead of print
Original articles (submitted)
Published online: 2021-04-12

Abstract

Background: Oxidative stress, endoplasmic reticulum stress (ER stress), and inflammation are the main leading factors in the pathogenesis of type 2 diabetes. Nuclear factor erythroid 2-related factor 2/ Kelch-like ECH-associated protein 1 (Nrf2/Keap1) is the chief regulator of the antioxidant defense system that protects the cells against reactive oxygen species (ROS). ER stress and inflammatory pathways are involved in the suppression or the activation of the Nrf2/Keap1 system. In this study, we aimed to explore the possible relationships of the main factors contributing to oxidative stress, endoplasmic reticulum stress, and inflammation in peripheral blood mononuclear cells (PBMCs) of diabetic patients. Methods: Levels of biological parameters, oxidative stress markers as well as the gene transcription of Nrf2, Keap1, p22phox, Chop1, Grp78, IL-6, and TNF- were analyzed in the PBMCs of 32 type 2 diabetic and 31 non-diabetic subjects. The correlation analysis was performed for the markers of oxidative stress with selected ER stress-related genes and pro-inflammatory cytokines. Results: Fasting blood sugar (P<0.0001), HbA1c (P<0.0001), serum triglycerides (P = 0.024), insulin (P = 0.003), and HOMA-IR (P = 0.001) were significantly higher in diabetic patients compared with non-diabetic subjects. Levels of malondialdehyde (MDA) and carbonyl content were higher in the diabetes group. Conversely, total thiol content, and ferric reduction of plasma was higher in the healthy group. The mRNA levels of Nrf2 were negatively correlated with Keap1 and IL-6 gene expression. We observed a significant positive correlation between mRNA levels of Chop1, Grp78, and Nrf2 transcription levels. Conclusion: The data of the present study suggest that the impaired function of the Nrf2/Keap1 system is associated with pathological factors such as ER stress and inflammation.

Abstract

Background: Oxidative stress, endoplasmic reticulum stress (ER stress), and inflammation are the main leading factors in the pathogenesis of type 2 diabetes. Nuclear factor erythroid 2-related factor 2/ Kelch-like ECH-associated protein 1 (Nrf2/Keap1) is the chief regulator of the antioxidant defense system that protects the cells against reactive oxygen species (ROS). ER stress and inflammatory pathways are involved in the suppression or the activation of the Nrf2/Keap1 system. In this study, we aimed to explore the possible relationships of the main factors contributing to oxidative stress, endoplasmic reticulum stress, and inflammation in peripheral blood mononuclear cells (PBMCs) of diabetic patients. Methods: Levels of biological parameters, oxidative stress markers as well as the gene transcription of Nrf2, Keap1, p22phox, Chop1, Grp78, IL-6, and TNF- were analyzed in the PBMCs of 32 type 2 diabetic and 31 non-diabetic subjects. The correlation analysis was performed for the markers of oxidative stress with selected ER stress-related genes and pro-inflammatory cytokines. Results: Fasting blood sugar (P<0.0001), HbA1c (P<0.0001), serum triglycerides (P = 0.024), insulin (P = 0.003), and HOMA-IR (P = 0.001) were significantly higher in diabetic patients compared with non-diabetic subjects. Levels of malondialdehyde (MDA) and carbonyl content were higher in the diabetes group. Conversely, total thiol content, and ferric reduction of plasma was higher in the healthy group. The mRNA levels of Nrf2 were negatively correlated with Keap1 and IL-6 gene expression. We observed a significant positive correlation between mRNA levels of Chop1, Grp78, and Nrf2 transcription levels. Conclusion: The data of the present study suggest that the impaired function of the Nrf2/Keap1 system is associated with pathological factors such as ER stress and inflammation.
Get Citation

Keywords

Reactive oxygen species, Type 2 diabetes, Oxidative stress, Endoplasmic reticulum Stress, Inflammation, Nrf2/keap1 system, PBMC

About this article
Title

The relationship between Nrf2/Keap1 system and endoplasmic reticulum stress and inflammatory markers in peripheral blood mononuclear cells of type 2 diabetic subjects

Journal

Clinical Diabetology

Issue

Ahead of print

Article type

Research paper

Published online

2021-04-12

DOI

10.5603/DK.a2021.0032

Keywords

Reactive oxygen species
Type 2 diabetes
Oxidative stress
Endoplasmic reticulum Stress
Inflammation
Nrf2/keap1 system
PBMC

Authors

Farshad Niazpour
Hosein Hoseini
ShadiSadat Seyyedebrahimi
Ensieh Nasli Esfahani
Reza Meshkani

References (43)
  1. Guariguata L, Whiting DR, Hambleton I, et al. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract. 2014; 103(2): 137–149.
  2. Cerf ME. Beta cell dysfunction and insulin resistance. Front Endocrinol (Lausanne). 2013; 4: 37.
  3. Tangvarasittichai S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes. 2015; 6(3): 456–480.
  4. Yki-Järvinen H. Pathophysiology of type 2 diabetes mellitus. Oxford Textbook of Endocrinology and Diabetes. 2011: 1740–1748.
  5. Emamgholipour S, Ebrahimi R, Bahiraee A, et al. Acetylation and insulin resistance: a focus on metabolic and mitogenic cascades of insulin signaling. Critical Reviews in Clinical Laboratory Sciences. 2020; 57(3): 196–214.
  6. Styskal J, Van Remmen H, Richardson A, et al. Oxidative stress and diabetes: what can we learn about insulin resistance from antioxidant mutant mouse models? Free Radic Biol Med. 2012; 52(1): 46–58.
  7. Wang X, Hai CX. ROS acts as a double-edged sword in the pathogenesis of type 2 diabetes mellitus: is Nrf2 a potential target for the treatment? Mini Rev Med Chem. 2011; 11(12): 1082–1092.
  8. Halliwell B. The wanderings of a free radical. Free Radic Biol Med. 2009; 46(5): 531–542.
  9. Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2007; 47: 89–116.
  10. Itoh K, Chiba T, Takahashi S, et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun. 1997; 236(2): 313–322.
  11. Bhakkiyalakshmi E, Sireesh D, Rajaguru P, et al. The emerging role of redox-sensitive Nrf2-Keap1 pathway in diabetes. Pharmacol Res. 2015; 91: 104–114.
  12. Motohashi H, Yamamoto M. Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med. 2004; 10(11): 549–557.
  13. Eizirik DL, Cardozo AK, Cnop M. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev. 2008; 29(1): 42–61.
  14. Bertolotti A, Zhang Y, Hendershot LM, et al. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol. 2000; 2(6): 326–332.
  15. Mozzini C, et al. Endoplasmic reticulum stress, NRF2 signalling and cardiovascular diseases in a nutshell. Current atherosclerosis reports, 2017. Current Atherosclerosis Reports. 2017; 19(8): 33.
  16. Lenin R, Sankaramoorthy A, Mohan V, et al. Altered immunometabolism at the interface of increased endoplasmic reticulum (ER) stress in patients with type 2 diabetes. J Leukoc Biol. 2015; 98(4): 615–622.
  17. Emmendoerffer A, Hecht M, Boeker T, et al. Role of inflammation in chemical-induced lung cancer. Toxicology Letters. 2000; 112-113: 185–191.
  18. Lemieux I, Pascot A, Almeras N, et al. Elevated C-reactive protein: another component of the atherothrombotic profile of abdominal obesity. Arteriosclerosis, thrombosis, and vascular biology, 2001. Arterioscler Thromb Vasc Biol. 2001; 21(6): 961–967.
  19. Ebrahimi R, Bahiraee A, Niazpour F, et al. The role of microRNAs in the regulation of insulin signaling pathway with respect to metabolic and mitogenic cascades: A review. J Cell Biochem. 2019; 120(12): 19290–19309.
  20. Devasagayam, T., K. Boloor, and T. Ramasarma, Methods for estimating lipid peroxidation: an analysis of merits and demerits. 2003.
  21. Benzie IF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of "antioxidant power": the FRAP assay. Anal Biochem. 1996; 239(1): 70–76.
  22. Dalle-Donne I, Rossi R, Giustarini D, et al. Protein carbonyl groups as biomarkers of oxidative stress. Clinica Chimica Acta. 2003; 329(1-2): 23–38.
  23. Winther JR, Thorpe C. Quantification of thiols and disulfides. Biochim Biophys Acta. 2014; 1840(2): 838–846.
  24. Adaikalakoteswari A, Balasubramanyam M, Rema M, et al. Differential gene expression of NADPH oxidase (p22phox) and hemoxygenase-1 in patients with Type 2 diabetes and microangiopathy. Diabet Med. 2006; 23(6): 666–674.
  25. Vairamon SJ, Babu M, Viswanathan V. Oxidative stress markers regulating the healing of foot ulcers in patients with type 2 diabetes. Wounds. 2009; 21(10): 273.
  26. Kumawat M, Pahwa M, Gahlaut V, et al. Status of antioxidant enzymes and lipid peroxidation in type 2 diabetes mellitus with micro vascular complications. The Open Endocrinology Journal. 2009; 3(1): 12–15.
  27. Sireesh D, Dhamodharan U, Ezhilarasi K, et al. Association of NF-E2 related factor 2 (nrf2) and inflammatory cytokines in recent onset type 2 diabetes mellitus. Sci Rep. 2018; 8(1): 5126.
  28. Huang X, Sun M, Li D, et al. Augmented NADPH oxidase activity and p22phox expression in monocytes underlie oxidative stress of patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2011; 91(3): 371–380.
  29. Duman BS, Oztürk M, Yilmazeri S, et al. Thiols, malonaldehyde and total antioxidant status in the Turkish patients with type 2 diabetes mellitus. Tohoku J Exp Med. 2003; 201(3): 147–155.
  30. Van Campenhout A, Van Campenhout C, Lagrou AR, et al. Impact of diabetes mellitus on the relationships between iron-, inflammatory- and oxidative stress status. Diabetes Metab Res Rev. 2006; 22(6): 444–454.
  31. Srivatsan R. Antioxidants and lipid peroxidation status in diabetic patients with and without complications. 2009.
  32. Pasaoglu H, Sancak B, Bukan N. Lipid peroxidation and resistance to oxidation in patients with type 2 diabetes mellitus. Tohoku J Exp Med. 2004; 203(3): 211–218.
  33. Zhong Q, Mishra M, Kowluru RA. Transcription factor Nrf2-mediated antioxidant defense system in the development of diabetic retinopathy. Invest Ophthalmol Vis Sci. 2013; 54(6): 3941–3948.
  34. Rabbani PS, Soares MA, Hameedi SG, et al. Dysregulation of nrf2/keap1 redox pathway in diabetes affects multipotency of stromal cells. Diabetes. 2019; 68(1): 141–155.
  35. Karbach S, Jansen T, Horke S, et al. Hyperglycemia and oxidative stress in cultured endothelial cells--a comparison of primary endothelial cells with an immortalized endothelial cell line. J Diabetes Complications. 2012; 26(3): 155–162.
  36. Volpe CM, Villar-Delfino PH, Dos Anjos PM, et al. Cellular death, reactive oxygen species (ROS) and diabetic complications. Cell Death Dis. 2018; 9(2): 119.
  37. Sharma R, Buras E, Terashima T, et al. Hyperglycemia induces oxidative stress and impairs axonal transport rates in mice. PLoS ONE. 2010; 5(10): e13463.
  38. Cao SS, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. Antioxid Redox Signal. 2014; 21(3): 396–413.
  39. Bravo R, Gutierrez T, Paredes F, et al. Endoplasmic reticulum: ER stress regulates mitochondrial bioenergetics. The International Journal of Biochemistry & Cell Biology. 2012; 44(1): 16–20.
  40. Visvikis-Siest S, Marteau JB, Samara A, et al. Peripheral blood mononuclear cells (PBMCs): a possible model for studying cardiovascular biology systems. Clin Chem Lab Med. 2007; 45(9): 1154–1168.
  41. Thimmulappa RK, Scollick C, Traore K, et al. Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide. Biochem Biophys Res Commun. 2006; 351(4): 883–889.
  42. Shanmugam G, Narasimhan M, Sakthivel R, et al. A biphasic effect of TNF-α in regulation of the Keap1/Nrf2 pathway in cardiomyocytes. Redox Biol. 2016; 9: 77–89.
  43. Mao L, Wang H, Qiao L, et al. Disruption of Nrf2 enhances the upregulation of nuclear factor-kappaB activity, tumor necrosis factor-α, and matrix metalloproteinase-9 after spinal cord injury in mice. Mediators Inflamm. 2010; 2010: 238321.

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

 

Wydawcą serwisu jest  "Via Medica sp. z o.o." sp.k., ul. Świętokrzyska 73, 80–180 Gdańsk

tel.:+48 58 320 94 94, faks:+48 58 320 94 60, e-mail:  viamedica@viamedica.pl