Skip to main content
SpringerLink
Log in

Fenofibrate ameliorates diabetic retinopathy by modulating Nrf2 signaling and NLRP3 inflammasome activation

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Oxidative stress and neuroinflammation contribute significantly to the development and progression of diabetic retinopathy. Fenofibrate has received great attention as it benefits diabetic patients by reducing retinal laser requirement. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a master regulator of anti-oxidative defense. Activation of nucleotide binding domain, leucine-rich repeat-containing receptor (NLR), pyrin domain-containing 3 (NLRP3) inflammasome plays a pivotal role in neuroinflammation. The purpose of this study is to determine whether fenofibrate protects retinas from oxidative damage and neuroinflammation via modulating the Nrf2 pathway and blocking NLRP3 inflammasome activation during diabetes. Diabetes is induced by intraperitoneal injection of streptozotocin in mice. Fenofibrate was given to mice in rodent chow. Upregulation of Nrf2 and NLRP3 inflammasome, enhanced ROS formation, and increased leukostasis and vascular leakage were observed in diabetic mouse retinas. Notably, Nrf2 and Caspase-1 were mainly colocalized with glutamine synthetase, one of the Mȕller cell markers. Fenofibrate further increased the expression of Nrf2 and its target gene NQO-1 and HO-1 and reduced ROS formation in diabetic retinas. In addition, retinal expression of NLRP3, Caspase-1 p20, IL-1β p17, and ICAM-1 were dramatically increased in vehicle-treated diabetic mice, which were abolished by fenofibrate intervention. Moreover, fenofibrate treatment also attenuated diabetes-induced retinal leukostasis and vascular leakage in mice. Taken together, fenofibrate attenuates oxidative stress and neuroinflammation in diabetic retinas, which is at least partially through modulating Nrf2 expression and NLRP3 inflammasome activation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Keech AC, Mitchell P, Summanen PA, O’Day J, Davis TM, Moffitt MS, Taskinen MR, Simes RJ, Tse D, Williamson E, Merrifield A, Laatikainen LT, d’Emden MC, Crimet DC, O’Connell RL, Colman PG, Investigators FS (2007) Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 370:1687–1697. https://doi.org/10.1016/S0140-6736(07)61607-9

    Article  PubMed  CAS  Google Scholar 

  2. Group AS, Group AES, Chew EY, Ambrosius WT, Davis MD, Danis RP, Gangaputra S, Greven CM, Hubbard L, Esser BA, Lovato JF, Perdue LH, Goff DC Jr., Cushman WC, Ginsberg HN, Elam MB, Genuth S, Gerstein HC, Schubart U, Fine LJ (2010) Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 363:233–244. https://doi.org/10.1056/NEJMoa1001288

    Article  CAS  Google Scholar 

  3. Noonan JE, Jenkins AJ, Ma JX, Keech AC, Wang JJ, Lamoureux EL (2013) An update on the molecular actions of fenofibrate and its clinical effects on diabetic retinopathy and other microvascular end points in patients with diabetes. Diabetes 62:3968–3975. https://doi.org/10.2337/db13-0800

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54:1615–1625

    Article  PubMed  CAS  Google Scholar 

  5. Cheng Y, Zhang J, Guo W, Li F, Sun W, Chen J, Zhang C, Lu X, Tan Y, Feng W, Fu Y, Liu GC, Xu Z, Cai L (2016) Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy. Free Radic Biol Med 93:94–109. https://doi.org/10.1016/j.freeradbiomed.2016.02.002

    Article  PubMed  CAS  Google Scholar 

  6. Ibarra-Lara L, Hong E, Soria-Castro E, Torres-Narvaez JC, Perez-Severiano F, Del Valle-Mondragon L, Cervantes-Perez LG, Ramirez-Ortega M, Pastelin-Hernandez GS, Sanchez-Mendoza A (2012) Clofibrate PPARalpha activation reduces oxidative stress and improves ultrastructure and ventricular hemodynamics in no-flow myocardial ischemia. J Cardiovasc Pharmacol 60:323–334. https://doi.org/10.1097/FJC.0b013e31826216ed

    Article  PubMed  CAS  Google Scholar 

  7. 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 83:1029–1041. https://doi.org/10.1038/ki.2012.439

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Chen WJ, Wu C, Xu Z, Kuse Y, Hara H, Duh EJ (2017) Nrf2 protects photoreceptor cells from photo-oxidative stress induced by blue light. Exp Eye Res 154:151–158. https://doi.org/10.1016/j.exer.2016.12.001

    Article  PubMed  CAS  Google Scholar 

  9. Ogura Y, Sutterwala FS, Flavell RA (2006) The inflammasome: first line of the immune response to cell stress. Cell 126:659–662. https://doi.org/10.1016/j.cell.2006.08.002

    Article  PubMed  CAS  Google Scholar 

  10. Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J (2010) Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol 11:136–140. https://doi.org/10.1038/ni.1831

    Article  PubMed  CAS  Google Scholar 

  11. Loukovaara S, Piippo N, Kinnunen K, Hytti M, Kaarniranta K, Kauppinen A (2017) NLRP3 inflammasome activation is associated with proliferative diabetic retinopathy. Acta Ophthalmol. https://doi.org/10.1111/aos.13427

    Article  PubMed  Google Scholar 

  12. Deng Y, Han X, Yao Z, Sun Y, Yu J, Cai J, Ren G, Jiang G, Han F (2017) PPARalpha agonist stimulated angiogenesis by improving endothelial precursor cell function via a NLRP3 inflammasome pathway. Cell Physiol Biochem 42:2255–2266. https://doi.org/10.1159/000479999

    Article  PubMed  CAS  Google Scholar 

  13. Zhong Y, Li J, Chen Y, Wang JJ, Ratan R, Zhang SX (2012) Activation of endoplasmic reticulum stress by hyperglycemia is essential for Muller cell-derived inflammatory cytokine production in diabetes. Diabetes 61:492–504. https://doi.org/10.2337/db11-0315

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Cheng R, Ding L, He X, Takahashi Y, Ma JX (2016) Interaction of PPARalpha with the canonic Wnt pathway in the regulation of renal fibrosis. Diabetes 65:3730–3743. https://doi.org/10.2337/db16-0426

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Li J, Wang JJ, Yu Q, Chen K, Mahadev K, Zhang SX (2010) Inhibition of reactive oxygen species by Lovastatin downregulates vascular endothelial growth factor expression and ameliorates blood-retinal barrier breakdown in db/db mice: role of NADPH oxidase 4. Diabetes 59:1528–1538. https://doi.org/10.2337/db09-1057

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Akiyama G, Azuchi Y, Guo X, Noro T, Kimura A, Harada C, Namekata K, Harada T (2017) Edaravone prevents retinal degeneration in adult mice following optic nerve injury. Invest Ophthalmol Vis Sci 58:4908–4914. https://doi.org/10.1167/iovs.17-22250

    Article  PubMed  Google Scholar 

  17. Li J, Wang JJ, Zhang SX (2011) Preconditioning with endoplasmic reticulum stress mitigates retinal endothelial inflammation via activation of X-box binding protein 1. J Biol Chem 286:4912–4921. https://doi.org/10.1074/jbc.M110.199729

    Article  PubMed  CAS  Google Scholar 

  18. Lewis GP, Fisher SK (2003) Up-regulation of glial fibrillary acidic protein in response to retinal injury: its potential role in glial remodeling and a comparison to vimentin expression. Int Rev Cytol 230:263–290

    Article  PubMed  CAS  Google Scholar 

  19. Du Y, Veenstra A, Palczewski K, Kern TS (2013) Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina. Proc Natl Acad Sci USA 110:16586–16591. https://doi.org/10.1073/pnas.1314575110

    Article  PubMed  Google Scholar 

  20. No Authors (1987) Indications for photocoagulation treatment of diabetic retinopathy: Diabetic Retinopathy Study Report no. 14. The Diabetic Retinopathy Study Research Group. Int Ophthalmol Clin 27:239–253

  21. No Authors (1991) Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 98:766–785

  22. Wei Y, Gong J, Xu Z, Duh EJ (2016) Nrf2 promotes reparative angiogenesis through regulation of NADPH oxidase-2 in oxygen-induced retinopathy. Free Radic Biol Med 99:234–243. https://doi.org/10.1016/j.freeradbiomed.2016.08.013

    Article  PubMed  CAS  Google Scholar 

  23. Wei Y, Gong J, Xu Z, Thimmulappa RK, Mitchell KL, Welsbie DS, Biswal S, Duh EJ (2015) Nrf2 in ischemic neurons promotes retinal vascular regeneration through regulation of semaphorin 6A. Proc Natl Acad Sci USA 112:E6927–E6936. https://doi.org/10.1073/pnas.1512683112

    Article  PubMed  CAS  Google Scholar 

  24. Xu Z, Wei Y, Gong J, Cho H, Park JK, Sung ER, Huang H, Wu L, Eberhart C, Handa JT, Du Y, Kern TS, Thimmulappa R, Barber AJ, Biswal S, Duh EJ (2014) NRF2 plays a protective role in diabetic retinopathy in mice. Diabetologia 57:204–213. https://doi.org/10.1007/s00125-013-3093-8

    Article  PubMed  CAS  Google Scholar 

  25. Inoue Y, Shimazawa M, Noda Y, Nagano R, Otsuka T, Kuse Y, Nakano Y, Tsuruma K, Nakagami Y, Hara H (2017) RS9, a novel Nrf2 activator, attenuates light-induced death of cells of photoreceptor cells and Muller glia cells. J Neurochem 141:750–765. https://doi.org/10.1111/jnc.14029

    Article  PubMed  CAS  Google Scholar 

  26. Sun Y, Xiu C, Liu W, Tao Y, Wang J, Qu YI (2016) Grape seed proanthocyanidin extract protects the retina against early diabetic injury by activating the Nrf2 pathway. Exp Ther Med 11:1253–1258. https://doi.org/10.3892/etm.2016.3033

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Park JS, Kang DH, Lee DH, Bae SH (2015) Fenofibrate activates Nrf2 through p62-dependent Keap1 degradation. Biochem Biophys Res Commun 465:542–547. https://doi.org/10.1016/j.bbrc.2015.08.056

    Article  PubMed  CAS  Google Scholar 

  28. Ding L, Cheng R, Hu Y, Takahashi Y, Jenkins AJ, Keech AC, Humphries KM, Gu X, Elliott MH, Xia X, Ma JX (2014) Peroxisome proliferator-activated receptor alpha protects capillary pericytes in the retina. Am J Pathol 184:2709–2720. https://doi.org/10.1016/j.ajpath.2014.06.021

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Chen Y, Hu Y, Lin M, Jenkins AJ, Keech AC, Mott R, Lyons TJ, Ma JX (2013) Therapeutic effects of PPARalpha agonists on diabetic retinopathy in type 1 diabetes models. Diabetes 62:261–272. https://doi.org/10.2337/db11-0413

    Article  PubMed  CAS  Google Scholar 

  30. Bringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P, Skatchkov SN, Osborne NN, Reichenbach A (2006) Muller cells in the healthy and diseased retina. Prog Retin Eye Res 25:397–424. https://doi.org/10.1016/j.preteyeres.2006.05.003

    Article  PubMed  CAS  Google Scholar 

  31. Sorrentino FS, Allkabes M, Salsini G, Bonifazzi C, Perri P (2016) The importance of glial cells in the homeostasis of the retinal microenvironment and their pivotal role in the course of diabetic retinopathy. Life Sci 162:54–59. https://doi.org/10.1016/j.lfs.2016.08.001

    Article  PubMed  CAS  Google Scholar 

  32. Moran EP, Wang Z, Chen J, Sapieha P, Smith LE, Ma JX (2016) Neurovascular cross talk in diabetic retinopathy: pathophysiological roles and therapeutic implications. Am J Physiol Heart Circ Physiol 311:H738–H749. https://doi.org/10.1152/ajpheart.00005.2016

    Article  PubMed  PubMed Central  Google Scholar 

  33. Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867. https://doi.org/10.1038/nature05485

    Article  PubMed  CAS  Google Scholar 

  34. Rampanelli E, Orso E, Ochodnicky P, Liebisch G, Bakker PJ, Claessen N, Butter LM, van den Bergh Weerman MA, Florquin S, Schmitz G, Leemans JC (2017) Metabolic injury-induced NLRP3 inflammasome activation dampens phospholipid degradation. Sci Rep 7:2861. https://doi.org/10.1038/s41598-017-01994-9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Chen W, Zhao M, Zhao S, Lu Q, Ni L, Zou C, Lu L, Xu X, Guan H, Zheng Z, Qiu Q (2017) Activation of the TXNIP/NLRP3 inflammasome pathway contributes to inflammation in diabetic retinopathy: a novel inhibitory effect of minocycline. Inflamm Res 66:157–166. https://doi.org/10.1007/s00011-016-1002-6

    Article  PubMed  CAS  Google Scholar 

  36. Yin Y, Chen F, Wang W, Wang H, Zhang X (2017) Resolvin D1 inhibits inflammatory response in STZ-induced diabetic retinopathy rats: Possible involvement of NLRP3 inflammasome and NF-kappaB signaling pathway. Mol Vis 23:242–250

    PubMed  PubMed Central  CAS  Google Scholar 

  37. Eastlake K, Banerjee PJ, Angbohang A, Charteris DG, Khaw PT, Limb GA (2016) Muller glia as an important source of cytokines and inflammatory factors present in the gliotic retina during proliferative vitreoretinopathy. Glia 64:495–506. https://doi.org/10.1002/glia.22942

    Article  PubMed  CAS  Google Scholar 

  38. Le YZ (2017) VEGF production and signaling in Muller glia are critical to modulating vascular function and neuronal integrity in diabetic retinopathy and hypoxic retinal vascular diseases. Vis Res. https://doi.org/10.1016/j.visres.2017.05.005

    Article  PubMed  Google Scholar 

Download references

Funding

This study was supported by NSFC Grants 81400427, 81460163, 81741058 and 81300786; Young Talent Scholar Grant 2016KJXX-12; FRFCU Grant xjj2015015; RFDP grant 20133601120012; Research Grants from Jiangxi Education Department GJJ14094, GJJ13175; Research Grants from Jiangxi Science and Technology Department 20142BDH80005, 20142BAB215029, 20132BAB205024. Parts of this study were orally presented at annual meeting of Asia-Pacific Academy of Ophthalmology.

Author information

Author notes

    Authors and Affiliations

    1. Department of Ophthalmology, Affiliated Eye Hospital of Nanchang University, 463 Bayi Road, Nanchang, 330006, Jiangxi, China

      Qiuping Liu, Fengjun Zhang, Xian Zhang, Jinglin Yi & Jingming Li

    2. Department of Physiology, Health Sciences Center, University of Oklahoma, 941 Stanton L. Young Blvd, Oklahoma City, OK, 73104, USA

      Rui Cheng & Jian-xing Ma

    Authors
    1. Qiuping Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Fengjun Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Xian Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Rui Cheng
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Jian-xing Ma
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Jinglin Yi
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Jingming Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Jinglin Yi or Jingming Li.

    Ethics declarations

    Conflict of interest

    The authors have no conflict of interests to declare.

    Additional information

    Qiuping Liu and Fengjun Zhang have contributed equally to this study.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Liu, Q., Zhang, F., Zhang, X. et al. Fenofibrate ameliorates diabetic retinopathy by modulating Nrf2 signaling and NLRP3 inflammasome activation. Mol Cell Biochem 445, 105–115 (2018). https://doi.org/10.1007/s11010-017-3256-x

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s11010-017-3256-x

    Keywords

    Search

    Navigation