Recombinant FGF21 Protects Against Blood-Brain Barrier Leakage Through Nrf2 Upregulation in Type 2 Diabetes Mice
- 460 Downloads
Blood-brain barrier (BBB) damage is a characteristic feature of diabetes mellitus pathology and plays significant roles in diabetes-associated neurological disorders. However, effective treatments for diabetes targeting BBB damage are yet to be developed. Fibroblast growth factor 21 (FGF21) is a potent regulator of lipid and glucose metabolism. In this study, we tested the hypothesis that recombinant FGF21 (rFGF21) administration may reduce type 2 diabetes (T2D)-induced BBB disruption via NF-E2-related factor-2 (Nrf2) upregulation. Our experimental results show that rFGF21 treatment significantly ameliorated BBB permeability and preserved junction protein expression in db/db mice in vivo. This protective effect was further confirmed by ameliorated transendothelial permeability and junction protein loss by rFGF21 under hyperglycemia and IL1β (HG-IL1β) condition in cultured human brain microvascular endothelial cells (HBMEC) in vitro. We further reveal that rFGF21 can activate FGF receptor 1 (FGFR1) that increases its binding with Kelch ECH-associating protein 1 (Keap1), a repressor of Nrf2, thereby reducing Keap1-Nrf2 interaction leading to Nrf2 release. These data suggest that rFGF21 administration may decrease T2D-induced BBB permeability, at least in part via FGFR1-Keap1-Nrf2 activation pathway. This study may provide an impetus for development of therapeutics targeting BBB damage in diabetes.
KeywordsFibroblast growth factor 21 (FGF21) Diabetes Blood-brain barrier (BBB) Hyperglycemia Inflammation FGFR1 Nrf2 Keap1
fibroblast growth factor 21
human brain microvascular endothelial cells
FGF receptor 1
NF-E2 related factor-2
Z.Y, L.L, I.C, and Y.J performed the study and analyzed the data. Z.Y and XY.W designed the experiment, analyzed the data, and wrote to the paper. X.L, XJ.W, and E.H.L helped in data analysis and paper writing. All authors have read and approved the manuscript.
This study was in part supported by the AHA Scientist Development Grant 15SDG25550035 (Yu Z), and National Institute of Health (NIH) 5R01NS099539 (Wang X).
Compliance with Ethical Standards
Conflict of Interest
The authors declare no competing financial interests in the manuscript.
All animal experiments were performed following protocols approved by the Massachusetts General Hospital Animal Care and Use Committee in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
- 3.Saczynski JS, Siggurdsson S, Jonsson PV, Eiriksdottir G, Olafsdottir E, Kjartansson O, Harris TB, van Buchem MA et al (2009) Glycemic status and brain injury in older individuals: the age gene/environment susceptibility-Reykjavik study. Diabetes Care 32(9):1608–1613. https://doi.org/10.2337/dc08-2300 CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Hawkins BT, Lundeen TF, Norwood KM, Brooks HL, Egleton RD (2007) Increased blood-brain barrier permeability and altered tight junctions in experimental diabetes in the rat: contribution of hyperglycaemia and matrix metalloproteinases. Diabetologia 50(1):202–211. https://doi.org/10.1007/s00125-006-0485-z CrossRefPubMedGoogle Scholar
- 8.Acharya NK, Levin EC, Clifford PM, Han M, Tourtellotte R, Chamberlain D, Pollaro M, Coretti NJ et al (2013) Diabetes and hypercholesterolemia increase blood-brain barrier permeability and brain amyloid deposition: beneficial effects of the LpPLA2 inhibitor darapladib. J Alzheimers Dis 35(1):179–198. https://doi.org/10.3233/JAD-122254 CrossRefPubMedGoogle Scholar
- 14.Wente W, Efanov AM, Brenner M, Kharitonenkov A, Koster A, Sandusky GE, Sewing S, Treinies I et al (2006) Fibroblast growth factor-21 improves pancreatic beta-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes 55(9):2470–2478. https://doi.org/10.2337/db05-1435 CrossRefPubMedGoogle Scholar
- 16.Wang Q, Yuan J, Yu Z, Lin L, Jiang Y, Cao Z, Zhuang P, Whalen MJ et al (2017) FGF21 attenuates high-fat diet-induced cognitive impairment via metabolic regulation and anti-inflammation of obese mice. Mol Neurobiol 55:4702–4717. https://doi.org/10.1007/s12035-017-0663-7 CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Lee JM, Calkins MJ, Chan K, Kan YW, Johnson JA (2003) Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J Biol Chem 278(14):12029–12038. https://doi.org/10.1074/jbc.M211558200 CrossRefPubMedGoogle Scholar
- 19.Kurochkin AV, Chernov BK, Kirpichnikov MP, Kutyshenko VP, Bruskov VI (1989) Complete assignment of signals in 1D and 2D H-NMR spectra of a 17-member oligonucleotide, a model symmetrical analog of lambda operators. Mol Biol (Mosk) 23(1):135–152Google Scholar
- 20.Cheng X, Siow RC, Mann GE (2011) Impaired redox signaling and antioxidant gene expression in endothelial cells in diabetes: a role for mitochondria and the nuclear factor-E2-related factor 2-Kelch-like ECH-associated protein 1 defense pathway. Antioxid Redox Signal 14(3):469–487. https://doi.org/10.1089/ars.2010.3283 CrossRefPubMedGoogle Scholar
- 24.Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M (2004) Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol 24(24):10941–10953. https://doi.org/10.1128/MCB.24.24.10941-10953.2004 CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Yang H, Feng A, Lin S, Yu L, Lin X, Yan X, Lu X, Zhang C (2018) Fibroblast growth factor-21 prevents diabetic cardiomyopathy via AMPK-mediated antioxidation and lipid-lowering effects in the heart. Cell Death Dis 9(2):227. https://doi.org/10.1038/s41419-018-0307-5 CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Cheng Y, Zhang J, Guo W, Li F, Sun W, Chen J, Zhang C, Lu X et al (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 CrossRefPubMedGoogle Scholar
- 27.Lin L, Wang Q, Qian K, Cao Z, Xiao J, Wang X, Li X, Yu Z (2017) bFGF protects against oxygen glucose deprivation/reoxygenation-induced endothelial monolayer permeability via S1PR1-dependent mechanisms. Mol Neurobiol 55:3131–3142. https://doi.org/10.1007/s12035-017-0544-0 CrossRefPubMedGoogle Scholar
- 35.Nguyen PT, Tsunematsu T, Yanagisawa S, Kudo Y, Miyauchi M, Kamata N, Takata T (2013) The FGFR1 inhibitor PD173074 induces mesenchymal-epithelial transition through the transcription factor AP-1. Br J Cancer 109(8):2248–2258. https://doi.org/10.1038/bjc.2013.550 CrossRefPubMedPubMedCentralGoogle Scholar
- 38.Arlt A, Sebens S, Krebs S, Geismann C, Grossmann M, Kruse ML, Schreiber S, Schafer H (2013) Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity. Oncogene 32(40):4825–4835. https://doi.org/10.1038/onc.2012.493 CrossRefPubMedGoogle Scholar
- 40.Cheng JC, Chang HM, Leung PC (2013) Transforming growth factor-beta1 inhibits trophoblast cell invasion by inducing Snail-mediated down-regulation of vascular endothelial-cadherin protein. J Biol Chem 288(46):33181–33192. https://doi.org/10.1074/jbc.M113.488866 CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Tu J, Zhang X, Zhu Y, Dai Y, Li N, Yang F, Zhang Q, Brann DW et al (2015) Cell-permeable peptide targeting the Nrf2-Keap1 interaction: a potential novel therapy for global cerebral ischemia. J Neurosci 35(44):14727–14739. https://doi.org/10.1523/JNEUROSCI.1304-15.2015 CrossRefPubMedPubMedCentralGoogle Scholar
- 47.Li G, Simon MJ, Cancel LM, Shi ZD, Ji X, Tarbell JM, Morrison B 3rd, Fu BM (2010) Permeability of endothelial and astrocyte cocultures: in vitro blood-brain barrier models for drug delivery studies. Ann Biomed Eng 38(8):2499–2511. https://doi.org/10.1007/s10439-010-0023-5 CrossRefPubMedPubMedCentralGoogle Scholar