Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Vitamin D Activates miR-126a-5p to Target GSK-3β and Alleviates Systemic Lupus Erythematosus in MRL/LPR Mice

Author(s): Min-Shu Zou, Qiu-Ju Song, Tai-Yong Yin, Hong-Tao Xu and Guo-Ming Nie*

Volume 24, Issue 14, 2023

Published on: 14 April, 2023

Page: [1803 - 1811] Pages: 9

DOI: 10.2174/1389201024666230330075550

Price: $65

conference banner
Abstract

Background: The etiology of systemic lupus erythematosus (SLE) is complex, and the disease is thus difficult to cure. In this regard, it has been established that SLE patients are characterized by differing levels of vitamin D-hydroxylation; however, the direct effects of vitamin D (VitD) in these patients remain unknown.

Objective: Therefore, we investigated the effects and mechanisms of action of VitD in the context of SLE.

Methods: The effects of VitD on MRL/LPR mice were studied by synthesizing glycogen synthase kinase-3β (GSK-3β)-interfering lentiviruses and transfecting with miR-126a-5p mimics. Changes in the body weight of mice were recorded for 6 weeks. Western blotting was performed to determine the levels of T-bet, GATA3, and GSK-3β protein expression, and qRT-PCR was performed to determine the levels of miR-126a-5p and GSK-3β mRNA expression. ELISA was performed to determine the levels of ANA, dsDNA, and snRNP/Sm in mice serum.

Results: GSK-3β and miR-126a-5p were expressed at high and low levels, respectively, in MRL/LPR mice. VitD (30 ng/kg) was found to reduce the expression of GSK-3β and increase miR-126a-5p expression, which targets GSK-3β. T-bet and GATA3 were found to be positively regulated by miR-126a-5p and VitD and negatively regulated by GSK-3β. The body weight of mice was not altered by VitD. ANA, dsDNA, and snRNP/Sm were positively regulated by miR- 126a-5p and VitD and negatively regulated by GSK-3β. The effects of GSK-3β were enhanced in response to the inhibition of miR-126a-5p expression.

Conclusion: VitD upregulated miR-126a-5p to target GSK-3β expression, thereby alleviating the SLE in MRL/LPR mice.

Keywords: Vitamin D, miR-126a-5p, GSK-3β, systemic lupus erythematosus, MRL/LPR mice, autoimmune disease.

« Previous Next »
Graphical Abstract

[1]
Blossom, S.J.; Gilbert, K.M. Epigenetic underpinnings of developmental immunotoxicity and autoimmune disease. Curr. Opin. Toxicol., 2018, 10, 23-30.
[http://dx.doi.org/10.1016/j.cotox.2017.11.013] [PMID: 30613805]
[2]
Cooper, G.S.; Bynum, M.L.K.; Somers, E.C. Recent insights in the epidemiology of autoimmune diseases: Improved prevalence estimates and understanding of clustering of diseases. J. Autoimmun., 2009, 33(3-4), 197-207.
[http://dx.doi.org/10.1016/j.jaut.2009.09.008] [PMID: 19819109]
[3]
Carter, E.E.; Barr, S.G.; Clarke, A.E. The global burden of SLE: Prevalence, health disparities and socioeconomic impact. Nat. Rev. Rheumatol., 2016, 12(10), 605-620.
[http://dx.doi.org/10.1038/nrrheum.2016.137] [PMID: 27558659]
[4]
Justiz Vaillant, AA.; Goyal, A.; Varacallo, M. Systemic Lupus Erythematosus. [Updated 2023 Feb 27]. In: StatPearls [Internet]; StatPearls Publishing; Treasure Island (FL), 2023. Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK535405/
[5]
Boddaert, J.; Huong, D.L.T.; Amoura, Z.; Wechsler, B.; Godeau, P.; Piette, J.C. Late-onset systemic lupus erythematosus: A personal series of 47 patients and pooled analysis of 714 cases in the literature. Medicine, 2004, 83(6), 348-359.
[http://dx.doi.org/10.1097/01.md.0000147737.57861.7c] [PMID: 15525847]
[6]
Binello, N.; Cancelli, C.; Passalacqua, S.; De Vito, F.; Lombardi, G.; Gambaro, G.; Manna, R. Use of intravenous immunoglobulin therapy at unconventional doses in refractory fulminant systemic lupus erythematosus. Eur. J. Case Rep. Intern. Med., 2018, 5(9), 1.
[http://dx.doi.org/10.12890/2018_000934] [PMID: 30756066]
[7]
Toko, H.; Tsuboi, H.; Umeda, N.; Honda, F.; Ohyama, A.; Takahashi, H.; Abe, S.; Yokosawa, M.; Asashima, H.; Hagiwara, S.; Hirota, T.; Kondo, Y.; Matsumoto, I.; Sumida, T. Intractable hemophagocytic syndrome associated with systemic lupus erythematosus resistant to corticosteroids and intravenous cyclophosphamide that was successfully treated with cyclosporine A. Intern. Med., 2018, 57(18), 2747-2752.
[8]
Touzot, M.; Terrier, C.S.P.; Faguer, S.; Masson, I.; François, H.; Couzi, L.; Hummel, A.; Quellard, N.; Touchard, G.; Jourde-Chiche, N.; Goujon, J.M.; Daugas, E. Proliferative lupus nephritis in the absence of overt systemic lupus erythematosus. Medicine, 2017, 96(48), e9017.
[http://dx.doi.org/10.1097/MD.0000000000009017] [PMID: 29310419]
[9]
Maestro, M.A.; Molnár, F.; Carlberg, C. Vitamin D and its synthetic analogs. J. Med. Chem., 2019, 62(15), 6854-6875.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00208] [PMID: 30916559]
[10]
Tabasi, N.; Rastin, M.; Mahmoudi, M.; Ghoryani, M.; Mirfeizi, Z.; Rabe, S.Z.T.; Reihani, H. Influence of vitamin D on cell cycle, apoptosis, and some apoptosis related molecules in systemic lupus erythematosus. Iran. J. Basic Med. Sci., 2015, 18(11), 1107-1111.
[PMID: 26949498]
[11]
Fakhfakh, R.; Feki, S.; Elleuch, A.; Neifar, M.; Marzouk, S.; Elloumi, N.; Hachicha, H.; Abida, O.; Bahloul, Z.; Ayadi, F.; Masmoudi, H. Vitamin D status and CYP27B 1‐1260 promoter polymorphism in Tunisian patients with systemic lupus erythematosus. Mol. Genet. Genomic Med., 2021, 9(3), e1618.
[http://dx.doi.org/10.1002/mgg3.1618] [PMID: 33594806]
[12]
Johnson, A.L.; Zinser, G.M.; Waltz, S.E. Vitamin D3-dependent VDR signaling delays ron-mediated breast tumorigenesis through suppression of β-catenin activity. Oncotarget, 2015, 6(18), 16304-16320.
[http://dx.doi.org/10.18632/oncotarget.4059] [PMID: 26008979]
[13]
Muralidhar, S.; Filia, A.; Nsengimana, J.; Poźniak, J.; O’Shea, S.J.; Diaz, J.M.; Harland, M.; Randerson-Moor, J.A.; Reichrath, J.; Laye, J.P.; van der Weyden, L.; Adams, D.J.; Bishop, D.T.; Newton-Bishop, J. Vitamin D-VDR signaling inhibits Wnt/β-catenin-mediated melanoma progression and promotes antitumor immunity. Cancer Res., 2019, 79(23), 5986-5998.
[http://dx.doi.org/10.1158/0008-5472.CAN-18-3927] [PMID: 31690667]
[14]
Lin, T.C.; Wu, J.Y.; Kuo, M.L.; Ou, L.S.; Yeh, K.W.; Huang, J.L. Correlation between disease activity of pediatric-onset systemic lupus erythematosus and level of vitamin D in Taiwan: A case-cohort study. J. Microbiol. Immunol. Infect., 2018, 51(1), 110-114.
[http://dx.doi.org/10.1016/j.jmii.2015.12.005] [PMID: 27147283]
[15]
Liu, D.; Fang, Y.X.; Wu, X.; Tan, W.; Zhou, W.; Zhang, Y.; Liu, Y.Q.; Li, G.Q. 1,25-(OH)2D3/Vitamin D receptor alleviates systemic lupus erythematosus by downregulating Skp2 and upregulating p27. Cell Commun. Signal., 2019, 17(1), 163.
[http://dx.doi.org/10.1186/s12964-019-0488-2] [PMID: 31823770]
[16]
He, X.J.; Ding, Y.; Xiang, W.; Dang, X.Q. Roles of 1,25(OH)2D3 and Vitamin D Receptor in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus by regulating the activation of CD4+ T cells and the PKCδ/ERK signaling pathway. Cell. Physiol. Biochem., 2016, 40(3-4), 743-756.
[http://dx.doi.org/10.1159/000453135] [PMID: 27915349]
[17]
Lopez-Pedrera, C.; Barbarroja, N.; Patiño-Trives, A.M.; Luque-Tévar, M.; Torres-Granados, C.; Aguirre-Zamorano, M.A.; Collantes-Estevez, E.; Pérez-Sánchez, C. Role of microRNAs in the development of cardiovascular disease in systemic autoimmune disorders. Int. J. Mol. Sci., 2020, 21(6), 2012.
[http://dx.doi.org/10.3390/ijms21062012] [PMID: 32188016]
[18]
Xu, H.; Chen, W.; Zheng, F.; Tang, D.; Liu, D.; Wang, G.; Xu, Y.; Yin, L.; Zhang, X.; Dai, Y. Reconstruction and analysis of the aberrant lncRNA-miRNA-mRNA network in systemic lupus erythematosus. Lupus, 2020, 29(4), 398-406.
[http://dx.doi.org/10.1177/0961203320908927] [PMID: 32070185]
[19]
Zeng, L.; Wu, J.; Liu, L.; Jiang, J.; Wu, H.; Zhao, M.; Lu, Q. Serum miRNA-371b-5p and miRNA-5100 act as biomarkers for systemic lupus erythematosus. Clin. Immunol., 2018, 196, 103-109.
[http://dx.doi.org/10.1016/j.clim.2018.10.004] [PMID: 30304699]
[20]
Long, H.; Wang, X.; Chen, Y.; Wang, L.; Zhao, M.; Lu, Q. Dysregulation of microRNAs in autoimmune diseases: Pathogenesis, biomarkers and potential therapeutic targets. Cancer Lett., 2018, 428, 90-103.
[http://dx.doi.org/10.1016/j.canlet.2018.04.016] [PMID: 29680223]
[21]
Garo, L.P.; Murugaiyan, G. Contribution of microRNAs to autoimmune diseases. Cell. Mol. Life Sci., 2016, 73(10), 2041-2051.
[http://dx.doi.org/10.1007/s00018-016-2167-4] [PMID: 26943802]
[22]
Picascia, A.; Grimaldi, V.; Pignalosa, O.; De Pascale, M.R.; Schiano, C.; Napoli, C. Epigenetic control of autoimmune diseases: From bench to bedside. Clin. Immunol., 2015, 157(1), 1-15.
[http://dx.doi.org/10.1016/j.clim.2014.12.013] [PMID: 25576661]
[23]
Livak, K.J.; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)). Method. Methods, 2001, 25(4), 402-408.
[24]
Dou, R.; Zhang, X.; Xu, X.; Wang, P.; Yan, B. Mesenchymal stem cell exosomal tsRNA-21109 alleviate systemic lupus erythematosus by inhibiting macrophage M1 polarization. Mol. Immunol., 2021, 139, 106-114.
[http://dx.doi.org/10.1016/j.molimm.2021.08.015] [PMID: 34464838]
[25]
Fayed, A.; Soliman, A.; Elgohary, R. Measuring serum sclerostin in Egyptian patients with systemic lupus erythematosus and evaluating its effect on disease activity: A case-control study. J. Clin. Rheumatol., 2021, 27(4), 161-167.
[PMID: 31895114]
[26]
Lu, S.; Lu, Y. miR-26a inhibits myocardial cell apoptosis in rats with acute myocardial infarction through GSK-3β pathway. Riv. Eur. Sci. Med. Farmacol., 2020, 24(5), 2659-2666.
[PMID: 32196616]
[27]
Yu, R.H.; Wang, L.M.; Hu, X.H. miR-135a inhibitor alleviates pulmonary arterial hypertension through β-Catenin/GSK-3β signaling pathway. Riv. Eur. Sci. Med. Farmacol., 2019, 23(21), 9574-9581.
[PMID: 31773709]
[28]
Qu, F.; Li, C.B.; Yuan, B.T.; Qi, W.; Li, H.L.; Shen, X.Z.; Zhao, G.; Wang, J.T.; Liu, Y.J. MicroRNA-26a induces osteosarcoma cell growth and metastasis via the Wnt/β-catenin pathway. Oncol. Lett., 2016, 11(2), 1592-1596.
[http://dx.doi.org/10.3892/ol.2015.4073] [PMID: 26893786]
[29]
Xu, Y.; He, Q.; Shen, Z.; Shu, X.; Wang, C.; Zhu, J.; Shi, L.; Du, L. MiR-126a-5p is involved in the hypoxia-induced endothelial-to-mesenchymal transition of neonatal pulmonary hypertension. Hypertens. Res., 2017, 40(6), 552-561.
[http://dx.doi.org/10.1038/hr.2017.2] [PMID: 28148930]
[30]
Du, X.; Zhu, M.; Zhang, T.; Wang, C.; Tao, J.; Yang, S.; Zhu, Y.; Zhao, W. The recombinant Eg. p29-mediated miR-126a-5p promotes the differentiation of mouse naïve CD4+ T cells via DLK1-mediated Notch1 signal pathway. Front. Immunol., 2022, 13, 773276.
[http://dx.doi.org/10.3389/fimmu.2022.773276] [PMID: 35211114]
[31]
Tan, Y.; Zhou, F.; Yang, D.; Zhang, X.; Zeng, M.; Wan, L. microRNA-126a-5p exerts neuroprotective effects on ischemic stroke via targeting NADPH oxidase 2. Neuropsychiatr. Dis. Treat., 2021, 17, 2089-2103.
[http://dx.doi.org/10.2147/NDT.S293611] [PMID: 34234438]
[32]
Zheng, H.; Guo, X.; Tian, Q.; Li, H.; Zhu, Y. Distinct role of Tim-3 in systemic lupus erythematosus and clear cell renal cell carcinoma. Int. J. Clin. Exp. Med., 2015, 8(5), 7029-7038.
[PMID: 26221240]
[33]
Li, H.; Zheng, Y.; Chen, L.; Lin, S. High titers of antinuclear antibody and the presence of multiple autoantibodies are highly suggestive of systemic lupus erythematosus. Sci. Rep., 2022, 12(1), 1687.
[http://dx.doi.org/10.1038/s41598-022-05807-6] [PMID: 35105907]
[34]
Hermann, H.; Fabrizio, P.; Raker, V.A.; Foulaki, K.; Hornig, H.; Brahms, H.; Lührmann, R. snRNP Sm proteins share two evolutionarily conserved sequence motifs which are involved in Sm protein-protein interactions. EMBO J., 1995, 14(9), 2076-2088.
[http://dx.doi.org/10.1002/j.1460-2075.1995.tb07199.x] [PMID: 7744013]

Rights & Permissions Print Cite
Article Metrics
28
2
Wayfinder Image
World Patient Safety Day
© 2024 Bentham Science Publishers | Privacy Policy