Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Research Article

BHTCM Protects Müller Cells from Diabetic Retinopathy by Reducing Abnormal Changes of Kir4.1 and AQP4, Suppressing VEGF and IL-1β, and Enhancing PEDF Production

Author(s): Haiyan Wu, Xuejun Xie*, Jie Yang, Xuewei Qin, Ya Mo, Li Wan and Mei Zhang*

Volume 20, Issue 8, 2023

Published on: 22 August, 2022

Page: [1046 - 1054] Pages: 9

DOI: 10.2174/1570180819666220610095408

Price: $65

Abstract

Background: In the diabetic condition, damage to the Müller cells contributes to the pathogenesis of diabetic retinopathy.

Aims: This study aimed to investigate the protective effect of Bushen Huoxue, Traditional Chinese Medicine (BHTCM), on Müller in diabetic retinopathological conditions.

Methods: Primary rat retinal Müller cells (RRMC) were isolated and cultured under high glucose (50 nmol/L). The advanced glycation end products (AGEs) and sodium dithionite were applied to treat highglucose administrated RRMC to mimic diabetic retinopathological conditions. The effects of BHTCM on diabetic retinopathological RRMC were evaluated. The expressions of aquaporin-4 (AQP4) and Kir4.1 were determined by double-labeling immunofluorescence and ELISA. Levels of vascular endothelial growth factor (VEGF), interleukin-1β (IL-1β) and pigment epithelium-derived factor (PEDF) were examined with ELISA. Lactate dehydrogenase (LDH) activity was also evaluated.

Results: Retinal Müller cells were successfully isolated and identified. RRMC treated with AGEs and sodium dithionite resulted in the increase of AQP4 and decrease of Kir4.1 in RRMC, increase of VEGF and IL-1β secretion, increase of LDH activity, decrease of PEDF secretion in culture medium, all of which, in a dose-dependent or time-dependent manner. Post treating RRMC with AGEs and dithionite, BHTCM reversed changes in expression of AQP4 and Kir4.1 in RRMC, and reversed VEGF levels, PEDF and IL-1β secretion in the culture medium. Moreover, BHTCM reversed the decrease of RRMC cell membrane integrity after AGEs and dithionite treatment.

Conclusion: BHTCM protected Müller cells from diabetic damage by reducing abnormal changes of Kir4.1 and AQP4, inhibiting VEGF and IL-1β, increasing PEDF production, and maintaining cell membrane integrity. Therefore, BHTCM is a potential drug for the treatment of diabetic retinopathy, which can correct the function of Müller cells.

Keywords: Bushen huoxue traditional Chinese medicine, Müller cells, diabetic retinopathy, advanced glycation end products, dithionite, diabetes.

« Previous Next »
Graphical Abstract

[1]
Toft-Kehler, A.K.; Skytt, D.M.; Kolko, M. A perspective on the müller cell-neuron metabolic partnership in the inner retina. Mol. Neurobiol., 2018, 55(6), 5353-5361.
[http://dx.doi.org/10.1007/s12035-017-0760-7] [PMID: 28929338]
[2]
Zhou, X.; Ai, S.; Chen, Z.; Li, C. Probucol promotes high glucose-induced proliferation and inhibits apoptosis by reducing reactive oxygen species generation in Müller cells. Int. Ophthalmol., 2019, 39(12), 2833-2842.
[http://dx.doi.org/10.1007/s10792-019-01130-8] [PMID: 31144240]
[3]
Kelly, K.; Wang, J.J.; Zhang, S.X. The unfolded protein response signaling and retinal Müller cell metabolism. Neural Regen. Res., 2018, 13(11), 1861-1870.
[http://dx.doi.org/10.4103/1673-5374.239431] [PMID: 30233053]
[4]
MacDonald, R.B.; Charlton-Perkins, M.; Harris, W.A. Mechanisms of Müller glial cell morphogenesis. Curr. Opin. Neurobiol., 2017, 47(1), 31-37.
[http://dx.doi.org/10.1016/j.conb.2017.08.005] [PMID: 28850820]
[5]
Dai, J.; Chen, H.; Chai, Y. Advanced glycation end products (AGEs) induce apoptosis of fibroblasts by activation of NLRP3 inflammasome via reactive oxygen species (ROS) signaling pathway. Med. Sci. Monit., 2019, 25(1), 7499-7508.
[http://dx.doi.org/10.12659/MSM.915806] [PMID: 31587010]
[6]
Puddu, A.; Viviani, G.L. Advanced glycation endproducts and diabetes. Beyond vascular complications. Endocr. Metab. Immune Disord. Drug Targets, 2011, 11(2), 132-140.
[http://dx.doi.org/10.2174/187153011795564115] [PMID: 21476962]
[7]
Wang, J.J.; Zhu, M.; Le, Y.Z. Functions of Müller cell-derived vascular endothelial growth factor in diabetic retinopathy. World J. Diabetes, 2015, 6(5), 726-733.
[http://dx.doi.org/10.4239/wjd.v6.i5.726] [PMID: 26069721]
[8]
Tien, T.; Zhang, J.; Muto, T.; Kim, D.; Sarthy, V.P.; Roy, S. High glucose induces mitochondrial dysfunction in retinal Müller cells: Implications for diabetic retinopathy. Invest. Ophthalmol. Vis. Sci., 2017, 58(7), 2915-2921.
[http://dx.doi.org/10.1167/iovs.16-21355] [PMID: 28586916]
[9]
Karbasforooshan, H.; Karimi, G. The role of SIRT1 in diabetic retinopathy. Biomed. Pharmacother., 2018, 97(1), 190-194.
[http://dx.doi.org/10.1016/j.biopha.2017.10.075] [PMID: 29091865]
[10]
Chen, G.; Ye, X.; Guan, Y.; Liu, W.; Du, J.; Yao, N.; Xu, X. Effects of bushen huoxue method for knee osteoarthritis: A protocol for systematic review and meta-analysis. Medicine (Baltimore), 2020, 99(24), e20659.
[http://dx.doi.org/10.1097/MD.0000000000020659] [PMID: 32541508]
[11]
Shen, W.; Luo, H.; Xu, L.; Wu, Z.; Chen, H.; Liu, Y.; Yu, L.; Hu, L.; Wang, B.; Luo, Y. Wnt5a mediates the effects of Bushen Huoxue decoction on the migration of bone marrow mesenchymal stem cells in vitro. Chin. Med., 2018, 13(1), 45.
[http://dx.doi.org/10.1186/s13020-018-0200-2] [PMID: 30181770]
[12]
Hu, L.; Liu, Y.; Wang, B.; Wu, Z.; Chen, Y.; Yu, L.; Zhu, J.; Shen, W.; Chen, C.; Chen, D.; Li, G.; Xu, L.; Luo, Y. MiR-539-5p negatively regulates migration of rMSCs induced by Bushen Huoxue decoction through targeting Wnt5a. Int. J. Med. Sci., 2019, 16(7), 998-1006.
[http://dx.doi.org/10.7150/ijms.33437] [PMID: 31341413]
[13]
Xie, X.J.; Song, M.X.; Zhang, M.; Qin, W.; Wan, L.; Fang, Y. Effect of bushen huoxue compound on retinal Müller cells in high glucose or AGEs conditions. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih, 2015, 35(6), 735-740.
[PMID: 26242129]
[14]
Wang, X.; Li, Y.; Xie, M.; Deng, L.; Zhang, M.; Xie, X. Urine metabolomics study of Bushen Huoxue Prescription on diabetic retinopathy rats by UPLC-Q-exactive Orbitrap-MS. Biomed. Chromatogr., 2020, 34(4), e4792.
[http://dx.doi.org/10.1002/bmc.4792] [PMID: 31907953]
[15]
Archer, S.L.; Hampl, V.; Nelson, D.P.; Sidney, E.; Peterson, D.A.; Weir, E.K. Dithionite increases radical formation and decreases vasoconstriction in the lung. Evidence that dithionite does not mimic alveolar hypoxia. Circ. Res., 1995, 77(1), 174-181.
[http://dx.doi.org/10.1161/01.RES.77.1.174] [PMID: 7788875]
[16]
Wang, L.; Yu, T.; Sun, H.; Liu, R.; Liu, Y. The effect of Bushen Huoxue method in treating glaucoma: A protocol for systematic review and meta-analysis. Medicine (Baltimore), 2020, 99(27), e21156.
[http://dx.doi.org/10.1097/MD.0000000000021156] [PMID: 32629752]
[17]
Yin, X.D.; Xue, X.O.; Wang, J.S.; Yang, W.; He, J.Q. Effect of Bushen Huoxue recipe on women with thin endomerial ovulation disorder and a rat model of thin endometrium resulted from kidney dificiency-related blood stasis. Gynecol. Endocrinol., 2020, 25(1), 1-5.
[PMID: 31187648]
[18]
Ding, J.; Tan, X.; Song, K.; Ma, W.; Xiao, J.; Song, Y.; Zhang, M. Bushen Huoxue recipe alleviates implantation loss in mice by enhancing estrogen-progesterone signals and promoting decidual angiogenesis through FGF2 during early pregnancy. Front. Pharmacol., 2018, 9(1), 437.
[http://dx.doi.org/10.3389/fphar.2018.00437] [PMID: 29867455]
[19]
Alex, A.; Luo, Q.; Mathew, D.; Di, R.; Bhatwadekar, A.D. Metformin corrects abnormal circadian rhythm and Kir4.1 channels in diabetes. Invest. Ophthalmol. Vis. Sci., 2020, 61(6), 46.
[http://dx.doi.org/10.1167/iovs.61.6.46] [PMID: 32572457]
[20]
Ozawa, Y.; Toda, E.; Kawashima, H.; Homma, K.; Osada, H.; Nagai, N.; Abe, Y.; Yasui, M.; Tsubota, K. Aquaporin 4 suppresses neural hyperactivity and synaptic fatigue and fine-tunes neurotransmission to regulate visual function in the mouse retina. Mol. Neurobiol., 2019, 56(12), 8124-8135.
[http://dx.doi.org/10.1007/s12035-019-01661-2] [PMID: 31190144]
[21]
Jung, E.; Kim, J. Aloin inhibits Müller cells swelling in a rat model of Thioacetamide-induced hepatic retinopathy. Molecules, 2018, 23(11), 2806.
[http://dx.doi.org/10.3390/molecules23112806] [PMID: 30380640]
[22]
Thompson, K.; Chen, J.; Luo, Q.; Xiao, Y.; Cummins, T.R.; Bhatwadekar, A.D. Advanced glycation end (AGE) product modification of laminin downregulates Kir4.1 in retinal Müller cells. PLoS One, 2018, 13(2), e0193280.
[http://dx.doi.org/10.1371/journal.pone.0193280] [PMID: 29474462]
[23]
You, Y.; Zhu, L.; Zhang, T.; Shen, T.; Fontes, A.; Yiannikas, C.; Parratt, J.; Barton, J.; Schulz, A.; Gupta, V.; Barnett, M.H.; Fraser, C.L.; Gillies, M.; Graham, S.L.; Klistorner, A. Evidence of Müller glial dysfunction in patients with Aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder. Ophthalmology, 2019, 126(6), 801-810.
[http://dx.doi.org/10.1016/j.ophtha.2019.01.016] [PMID: 30711604]
[24]
Li, X.M.; Wendu, R.L.; Yao, J.; Ren, Y.; Zhao, Y.X.; Cao, G.F.; Qin, J.; Yan, B. Abnormal glutamate metabolism in the retina of aquaporin 4 (AQP4) knockout mice upon light damage. Neurol. Sci., 2014, 35(6), 847-853.
[http://dx.doi.org/10.1007/s10072-013-1610-7] [PMID: 24368741]
[25]
Pisani, F.; Cammalleri, M.; Dal Monte, M.; Locri, F.; Mola, M.G.; Nicchia, G.P.; Frigeri, A.; Bagnoli, P.; Svelto, M. Potential role of the methylation of VEGF gene promoter in response to hypoxia in oxygen-induced retinopathy: Beneficial effect of the absence of AQP4. J. Cell. Mol. Med., 2018, 22(1), 613-627.
[http://dx.doi.org/10.1111/jcmm.13348] [PMID: 28940930]
[26]
Qin, Y.; Xu, G.; Fan, J.; Witt, R.E.; Da, C. High-salt loading exacerbates increased retinal content of aquaporins AQP1 and AQP4 in rats with diabetic retinopathy. Exp. Eye Res., 2009, 89(5), 741-747.
[http://dx.doi.org/10.1016/j.exer.2009.06.020] [PMID: 19596320]
[27]
Zhao, Y.; Singh, R.P. The role of anti-vascular endothelial growth factor (anti-VEGF) in the management of proliferative diabetic retinopathy. Drugs Context, 2018, 7(1), 212532.
[http://dx.doi.org/10.7573/dic.212532] [PMID: 30181760]
[28]
Cheung, N.; Wong, I.Y.; Wong, T.Y. Ocular anti-VEGF therapy for diabetic retinopathy: Overview of clinical efficacy and evolving applications. Diabetes Care, 2014, 37(4), 900-905.
[http://dx.doi.org/10.2337/dc13-1990] [PMID: 24652721]
[29]
Simó, R.; Sundstrom, J.M.; Antonetti, D.A. Ocular Anti-VEGF therapy for diabetic retinopathy: The role of VEGF in the pathogenesis of diabetic retinopathy. Diabetes Care, 2014, 37(4), 893-899.
[http://dx.doi.org/10.2337/dc13-2002] [PMID: 24652720]
[30]
Zhao, M.; Sun, Y.; Jiang, Y. Anti-VEGF therapy is not a magic bullet for diabetic retinopathy. Eye (Lond.), 2020, 34(4), 609-610.
[http://dx.doi.org/10.1038/s41433-019-0652-3] [PMID: 31659284]
[31]
Cao, G.; Xu, X.; Wang, C.; Zhang, S. Sequence effect in the treatment of proliferative diabetic retinopathy with intravitreal ranibizumab and panretinal photocoagulation. Eur. J. Ophthalmol., 2020, 30(1), 34-39.
[http://dx.doi.org/10.1177/1120672118812270] [PMID: 30539668]
[32]
Rodrigues, M.; Xin, X.; Jee, K.; Babapoor-Farrokhran, S.; Kashiwabuchi, F.; Ma, T.; Bhutto, I.; Hassan, S.J.; Daoud, Y.; Baranano, D.; Solomon, S.; Lutty, G.; Semenza, G.L.; Montaner, S.; Sodhi, A. VEGF secreted by hypoxic Müller cells induces MMP-2 expression and activity in endothelial cells to promote retinal neovascularization in proliferative diabetic retinopathy. Diabetes, 2013, 62(11), 3863-3873.
[http://dx.doi.org/10.2337/db13-0014] [PMID: 23884892]
[33]
Elahy, M.; Baindur-Hudson, S.; Cruzat, V.F.; Newsholme, P.; Dass, C.R. Mechanisms of PEDF-mediated protection against reactive oxygen species damage in diabetic retinopathy and neuropathy. J. Endocrinol., 2014, 222(3), R129-R139.
[http://dx.doi.org/10.1530/JOE-14-0065] [PMID: 24928938]
[34]
Liu, Y.; Leo, L.F.; McGregor, C.; Grivitishvili, A.; Barnstable, C.J.; Tombran-Tink, J. Pigment epithelium-derived factor (PEDF) peptide eye drops reduce inflammation, cell death and vascular leakage in diabetic retinopathy in Ins2(Akita) mice. Mol. Med., 2012, 18(1), 1387-1401.
[http://dx.doi.org/10.2119/molmed.2012.00008] [PMID: 23019073]
[35]
Omri, S.; Tahiri, H.; Pierre, W.C.; Desjarlais, M.; Lahaie, I.; Loiselle, S.E.; Rezende, F.; Lodygensky, G.; Hebert, T.E.; Ong, H.; Chemtob, S. Propranolol attenuates proangiogenic activity of mononuclear phagocytes: Implication in choroidal neovascularization. Invest. Ophthalmol. Vis. Sci., 2019, 60(14), 4632-4642.
[http://dx.doi.org/10.1167/iovs.18-25502] [PMID: 31682714]
[36]
Figueroa, A.G.; McKay, B.S. GPR143 signaling and retinal degeneration. Adv. Exp. Med. Biol., 2019, 1185(1), 15-19.
[http://dx.doi.org/10.1007/978-3-030-27378-1_3] [PMID: 31884582]
[37]
Sun, Y.; Wang, D.; Ye, F.; Hu, D.N.; Liu, X.; Zhang, L.; Gao, L.; Song, E.; Zhang, D.Y. Elevated cell proliferation and VEGF production by high-glucose conditions in Müller cells involve XIAP. Eye (Lond.), 2013, 27(11), 1299-1307.
[http://dx.doi.org/10.1038/eye.2013.158] [PMID: 23928877]
[38]
Chen, J.F.; Luo, Q.H.; Huang, C.; Liu, W.T.; Zeng, W.; Gao, Q.; Chen, P.; Chen, B.; Chen, Z.L. Expression of VEGF and PEDF in early-stage retinopathy in diabetic Macaca mulatta. Nan Fang Yi Ke Da Xue Xue Bao, 2017, 37(9), 1217-1221.
[PMID: 28951365]
[39]
Xie, T.Y.; Yan, W.; Lou, J.; Chen, X.Y. Effect of ozone on vascular endothelial growth factor (VEGF) and related inflammatory cytokines in rats with diabetic retinopathy. Genet. Mol. Res., 2016, 15(2), 15027558.
[http://dx.doi.org/10.4238/gmr.15027558] [PMID: 27323014]
[40]
Demircan, N.; Safran, B.G.; Soylu, M.; Ozcan, A.A.; Sizmaz, S. Determination of vitreous interleukin-1 (IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy. Eye (Lond.), 2006, 20(12), 1366-1369.
[http://dx.doi.org/10.1038/sj.eye.6702138] [PMID: 16284605]
[41]
Capitão, M.; Soares, R. Angiogenesis and inflammation crosstalk in diabetic retinopathy. J. Cell. Biochem., 2016, 117(11), 2443-2453.
[http://dx.doi.org/10.1002/jcb.25575] [PMID: 27128219]
[42]
Rayamajhi, M.; Zhang, Y.; Miao, E.A. Detection of pyroptosis by measuring released lactate dehydrogenase activity. Methods Mol. Biol., 2013, 1040(1), 85-90.
[http://dx.doi.org/10.1007/978-1-62703-523-1_7] [PMID: 23852598]
[43]
Bigl, K.; Schmitt, A.; Meiners, I.; Münch, G.; Arendt, T. Comparison of results of the CellTiter Blue, the tetrazolium (3-[4,5-dimethylthioazol-2-yl]-2,5-diphenyl tetrazolium bromide), and the lactate dehydrogenase assay applied in brain cells after exposure to advanced glycation endproducts. Toxicol. In Vitro, 2007, 21(5), 962-971.
[http://dx.doi.org/10.1016/j.tiv.2007.02.003] [PMID: 17391910]

Rights & Permissions Print Cite
Article Metrics
1
© 2024 Bentham Science Publishers | Privacy Policy