Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

Neuritin Alleviates Diabetic Retinopathy by Regulating Endoplasmic Reticulum Stress in Rats

Author(s): Shu Wen, Meng Hu, Changzheng Chen, Zhen Li and Guoli Liu*

Volume 27, Issue 16, 2024

Published on: 03 January, 2024

Page: [2454 - 2461] Pages: 8

DOI: 10.2174/0113862073275316231123060640

Price: $65

Abstract

Background: Neuritin, a small-molecule neurotrophic factor, maintains neuronal cell activity, inhibits apoptosis, promotes process growth, and regulates neural progenitor cell differentiation, migration, and synaptic maturation. Neuritin helps retinal ganglion cells (RGCs) survive optic nerve injury in rats and regenerate axons. However, the role of Neuritin in Diabetic retinopathy (DR) is unclear.

Objective: This study is intended to investigate the effect and mechanism of Neuritin in DR. For this purpose, we established DR rat models and injected Neuritin into them. This study provides a potential treatment for diabetic retinopathy.

Methods: The rat model of DR was established by streptozotocin (STZ) injection, and the effect of Neuritin on DR was detected by intravitreal injection. Histological analysis was performed by H&E and TUNEL methods. The mRNA and protein expressions of endoplasmic reticulum stress (ERS) pathway-related transcription factors were detected by qRT-PCR and western blot. The blood-retinal barrier (BRB) function was assessed using the patch-clamp technique and Evans blue leakage assay.

Results: Neuritin significantly improved the retinal structure, restrained the apoptosis of retinal cells, and protected the normal function of BRB in DR model rats. Mechanistically, Neuritin may function by inhibiting the expression of GRP78, ASK1, Caspase-12, VEGF, and so on.

Conclusion: Our results indicate that Neuritin alleviates retinal damage in DR rats via the inactive endoplasmic reticulum pathway. Our study provides a potential treatment for DR.

« Previous
Graphical Abstract

[1]
Kropp, M.; Golubnitschaja, O.; Mazurakova, A.; Koklesova, L.; Sargheini, N.; Vo, T.T.K.S.; de Clerck, E.; Polivka, J., Jr; Potuznik, P.; Polivka, J.; Stetkarova, I.; Kubatka, P.; Thumann, G. Diabetic retinopathy as the leading cause of blindness and early predictor of cascading complications—risks and mitigation. EPMA J., 2023, 14(1), 21-42.
[http://dx.doi.org/10.1007/s13167-023-00314-8] [PMID: 36866156]
[2]
Stitt, A.W.; Curtis, T.M.; Chen, M.; Medina, R.J.; McKay, G.J.; Jenkins, A.; Gardiner, T.A.; Lyons, T.J.; Hammes, H.P.; Simó, R.; Lois, N. The progress in understanding and treatment of diabetic retinopathy. Prog. Retin. Eye Res., 2016, 51, 156-186.
[http://dx.doi.org/10.1016/j.preteyeres.2015.08.001] [PMID: 26297071]
[3]
Pires, R.; Avila, S.; Jelinek, H.F.; Wainer, J.; Valle, E.; Rocha, A. Beyond lesion-based diabetic retinopathy: A direct approach for referral. IEEE J. Biomed. Health Inform., 2017, 21(1), 193-200.
[http://dx.doi.org/10.1109/JBHI.2015.2498104] [PMID: 26561488]
[4]
Brownlee, M. The pathobiology of diabetic complications: A unifying mechanism. Diabetes, 2005, 54(6), 1615-1625.
[http://dx.doi.org/10.2337/diabetes.54.6.1615] [PMID: 15919781]
[5]
Suarez, S.; McCollum, G.W.; Jayagopal, A.; Penn, J.S. High glucose-induced retinal pericyte apoptosis depends on association of gapdh and siah1. J. Biol. Chem., 2015, 290(47), 28311-28320.
[http://dx.doi.org/10.1074/jbc.M115.682385] [PMID: 26438826]
[6]
Rafael, S.; Cristina, H. Advances in the medical treatment of diabetic retinopathy. Diabetes Care, 2009, 32(8), 1556.
[http://dx.doi.org/10.2337/dc09-0565] [PMID: 19638526]
[7]
Nickells, R.W. Apoptosis of retinal ganglion cells in glaucoma: An update of the molecular pathways involved in cell death. Surv. Ophthalmol., 1999, 43(Suppl. 1), S151-S161.
[http://dx.doi.org/10.1016/S0039-6257(99)00029-6] [PMID: 10416758]
[8]
Feng, I-Che. Cantharidic acid induces apoptosis through the p38 MAPK signaling pathway in human hepatocellular carcinoma. Environ. Toxicol., 2018.
[9]
Faitova, J.; Krekac, D.; Hrstka, R.; Vojtesek, B. Endoplasmic reticulum stress and apoptosis. Cell. Mol. Biol. Lett., 2006, 11(4), 488-505.
[http://dx.doi.org/10.2478/s11658-006-0040-4] [PMID: 16977377]
[10]
Gladwyn-Ng, I.; Cordón-Barris, L.; Alfano, C.; Creppe, C.; Couderc, T.; Morelli, G.; Thelen, N.; America, M.; Bessières, B.; Encha-Razavi, F.; Bonnière, M.; Suzuki, I.K.; Flamand, M.; Vanderhaeghen, P.; Thiry, M.; Lecuit, M.; Nguyen, L. Stress-induced unfolded protein response contributes to Zika virus–associated microcephaly. Nat. Neurosci., 2018, 21(1), 63-71.
[http://dx.doi.org/10.1038/s41593-017-0038-4] [PMID: 29230053]
[11]
Kong, D.Q.; Li, L.; Liu, Y.; Zheng, G.Y. Association between endoplasmic reticulum stress and risk factors of diabetic retinopathy. Int. J. Ophthalmol., 2018, 11(10), 1704-1710.
[PMID: 30364130]
[12]
Lie, Z.; Yali, Z.; Yancheng, D. Experimental study of salubrinal protecting human colon cancer cell line ht29 cell endoplasmic reticulum stress apoptosis. Chi. Arch. Trad. Chi. Med., 2019.
[13]
Zhang, H.; He, X.; Wang, Y.; Sun, X.; Zhu, L.; Lei, C.; Yin, J.; Li, X.; Hou, F.; He, W.; Zhao, D. Neuritin attenuates early brain injury in rats after experimental subarachnoid hemorrhage. Int. J. Neurosci., 2017, 127(12), 1087-1095.
[http://dx.doi.org/10.1080/00207454.2017.1337013] [PMID: 28562156]
[14]
Cunha-Vaz, J.; Bernardes, R.; Lobo, C. Blood-retinal barrier. Eur. J. Ophthalmol., 2011, 21(6_suppl)(Suppl.6), 3-9.
[http://dx.doi.org/10.5301/EJO.2010.6049] [PMID: 23264323]
[15]
Singh, R.K.; Devi, S.; Prasad, D.N. Synthesis, physicochemical and biological evaluation of 2-amino-5-chlorobenzophenone derivatives as potent skeletal muscle relaxants. Arab. J. Chem., 2015, 8(3), 307-312.
[http://dx.doi.org/10.1016/j.arabjc.2011.11.013]
[16]
Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Synthesis in vitro/in vivo evaluation and in silico physicochemical study of prodrug approach for brain targeting of alkylating agent. Med. Chem. Res., 2013, 22(11), 5324-5336.
[http://dx.doi.org/10.1007/s00044-013-0537-0]
[17]
Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Synthesis, physicochemical properties and kinetic study of bis(2-chloroethyl)amine as cytotoxic agent for brain delivery. Arab. J. Chem., 2015, 8, 380-387.
[http://dx.doi.org/10.1016/j.arabjc.2012.11.005]
[18]
Becker, S.; Wang, H.; Simmons, A.B.; Suwanmanee, T.; Stoddard, G.J.; Kafri, T.; Hartnett, M.E. Targeted knockdown of overexpressed VEGFA or VEGF164 in Müller cells maintains retinal function by triggering different signaling mechanisms. Sci. Rep., 2018, 8(1), 2003.
[http://dx.doi.org/10.1038/s41598-018-20278-4] [PMID: 29386650]
[19]
Le, Y.Z. VEGF production and signaling in Müller glia are critical to modulating vascular function and neuronal integrity in diabetic retinopathy and hypoxic retinal vascular diseases. Vision Res., 2017, 139, 108-114.
[http://dx.doi.org/10.1016/j.visres.2017.05.005] [PMID: 28601428]
[20]
Broughton, B.R.S.; Reutens, D.C.; Sobey, C.G. Apoptotic mechanisms after cerebral ischemia. Stroke, 2009, 40(5), e331-e339.
[http://dx.doi.org/10.1161/STROKEAHA.108.531632] [PMID: 19182083]
[21]
Yao, J.; Zhao, Q.; Lu, J.; Mei, Y. Functions and the related signaling pathways of the neurotrophic factor neuritin. Acta Pharmacol. Sin., 2018, 39(9), 1414-1420.
[http://dx.doi.org/10.1038/aps.2017.197] [PMID: 29595190]
[22]
Zhang, Y.; Zhang, S.; Xian, L.; Tang, J.; Zhu, J.; Cui, L.; Li, S.; Yang, L.; Huang, J. Expression and purification of recombinant human neuritin from Pichia pastoris and a partial analysis of its neurobiological activity in vitro. Appl. Microbiol. Biotechnol., 2015, 99(19), 8035-8043.
[http://dx.doi.org/10.1007/s00253-015-6649-3] [PMID: 26048470]
[23]
Loebrich, S.; Nedivi, E. The function of activity-regulated genes in the nervous system. Physiol. Rev., 2009, 89, 1079-1103.
[http://dx.doi.org/10.1152/physrev.00013.2009]
[24]
Sharma, T.P.; Liu, Y.; Wordinger, R.J.; Pang, I-H.; Clark, A.F. Neuritin 1 promotes retinal ganglion cell survival and axonal regeneration following optic nerve crush. Cell Death Dis., 2015, 6(2), e1661.
[http://dx.doi.org/10.1038/cddis.2015.22] [PMID: 25719245]
[25]
Srinivasan, K.; Patole, P.S.; Kaul, C.L.; Ramarao, P. Reversal of glucose intolerance by by pioglitazone in high fat diet-fed rats. Methods Find. Exp. Clin. Pharmacol., 2004, 26(5), 327-333.
[http://dx.doi.org/10.1358/mf.2004.26.5.831322] [PMID: 15319810]
[26]
Li, J.; Wang, J.J.; Yu, Q.; Wang, M.; Zhang, S.X. Endoplasmic reticulum stress is implicated in retinal inflammation and diabetic retinopathy. FEBS Lett., 2009, 583(9), 1521-1527.
[http://dx.doi.org/10.1016/j.febslet.2009.04.007] [PMID: 19364508]
[27]
Kong, D.Q.; Li, L.; Liu, Y.; Zheng, G.Y. Association between endoplasmic reticulum stress and risk factors of diabetic retinopathy. Int. J. Ophthalmol., 2018, 11(10), 1704.
[http://dx.doi.org/10.18240/ijo.2018.10.20] [PMID: 30364130]
[28]
Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Design, synthesis and antiproliferative activity of benzodiazepine-mustard conjugates as potential brain antitumour agents. J. Saudi Chem. Soc., 2017, 21(S1), S86-S93.
[http://dx.doi.org/10.1016/j.jscs.2013.10.004]
[29]
Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R.; Bhardwaj, T.R. Design, synthesis, chemical and biological evaluation of brain targeted alkylating agent using reversible redox prodrug approach. Arab. J. Chem., 2017, 10(3), 420-429.
[http://dx.doi.org/10.1016/j.arabjc.2013.12.008]
[30]
Wong, T.Y.; Cheung, C.M.G.; Larsen, M.; Sharma, S.; Simó, R. Diabetic retinopathy. Nat. Rev. Dis. Primers, 2016, 2(1), 16012.
[http://dx.doi.org/10.1038/nrdp.2016.12] [PMID: 27159554]
[31]
Wilkinson, C.P.; Ferris, F.L., III; Klein, R.E.; Lee, P.P.; Agardh, C.D.; Davis, M.; Dills, D.; Kampik, A.; Pararajasegaram, R.; Verdaguer, J.T. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology, 2003, 110(9), 1677-1682.
[http://dx.doi.org/10.1016/S0161-6420(03)00475-5] [PMID: 13129861]
[32]
Antcliff, R.J.; Marshall, J. The pathogenesis of edema in diabetic maculopathy. Semin. Ophthalmol., 1999, 14(4), 223-232.
[http://dx.doi.org/10.3109/08820539909069541] [PMID: 10758223]
[33]
Bhagat, N.; Grigorian, R.A.; Tutela, A.; Zarbin, M.A. Diabetic macular edema: Pathogenesis and treatment. Surv. Ophthalmol., 2009, 54(1), 1-32.
[http://dx.doi.org/10.1016/j.survophthal.2008.10.001] [PMID: 19171208]
[34]
Dhiman, A.; Sharma, R.; Singh, R.K. Target-based anticancer indole derivatives and insight into structure‒activity relationship: A mechanistic review update (2018–2021). Acta Pharm. Sin. B, 2022, 12(7), 3006-3027.
[http://dx.doi.org/10.1016/j.apsb.2022.03.021] [PMID: 35865090]
[35]
Joyce, M.A.; Walters, K.A.; Lamb, S.E.; Yeh, M.M.; Zhu, L.F.; Kneteman, N.; Doyle, J.S.; Katze, M.G.; Tyrrell, D.L. HCV induces oxidative and ER stress, and sensitizes infected cells to apoptosis in SCID/Alb-uPA mice. PLoS Pathog., 2009, 5(2), e1000291.
[http://dx.doi.org/10.1371/journal.ppat.1000291] [PMID: 19242562]
[36]
Allen, D.A.; Yaqoob, M.M.; Harwood, S.M. Mechanisms of high glucose-induced apoptosis and its relationship to diabetic complications. J. Nutr. Biochem., 2005, 16(12), 705-713.
[http://dx.doi.org/10.1016/j.jnutbio.2005.06.007] [PMID: 16169208]
[37]
Kong, F.J.; Ma, L.L.; Guo, J.J.; Xu, L.H.; Li, Y.; Qu, S. Endoplasmic reticulum stress/autophagy pathway is involved in diabetes-induced neuronal apoptosis and cognitive decline in mice. Clin. Sci., 2018, 132(1), 111-125.
[http://dx.doi.org/10.1042/CS20171432]
[38]
Brostrom, C.O.; Brostrom, M.A. Regulation of translational initiation during cellular responses to stress. Prog. Nucleic Acid Res. Mol. Biol., 1997, 58, 79-125.
[http://dx.doi.org/10.1016/S0079-6603(08)60034-3] [PMID: 9308364]
[39]
Kim, Y.K.; Kim, K.S.; Lee, A.S. Regulation of the glucose‐regulated protein genes by β‐mercaptoethanol requires de novo protein synthesis and correlates with inhibition of protein glycosylation. J. Cell. Physiol., 1987, 133(3), 553-559.
[http://dx.doi.org/10.1002/jcp.1041330317] [PMID: 3693412]
[40]
Little, E.; Ramakrishnan, M.; Roy, B.; Gazit, G.; Lee, A.S. The glucose-regulated proteins (GRP78 and GRP94): functions, gene regulation, and applications. Crit. Rev. Eukaryot. Gene Expr., 1994, 4(1), 1-18.
[http://dx.doi.org/10.1615/CritRevEukarGeneExpr.v4.i1.10] [PMID: 7987045]
[41]
Wooden, S.K.; Li, L.J.; Navarro, D.; Qadri, I.; Pereira, L.; Lee, A.S. Transactivation of the grp78 promoter by malfolded proteins, glycosylation block, and calcium ionophore is mediated through a proximal region containing a CCAAT motif which interacts with CTF/NF-I. Mol. Cell. Biol., 1991, 11(11), 5612-5623.
[PMID: 1656235]
[42]
Putz, U.; Harwell, C.; Nedivi, E. Soluble CPG15 expressed during early development rescues cortical progenitors from apoptosis. Nat. Neurosci., 2005, 8(3), 322-331.
[http://dx.doi.org/10.1038/nn1407] [PMID: 15711540]
[43]
Fujino, T; Wu, Z; Lin, WC cpgl5 and cpg15-2 constitute a family of activity-regulated ligands expressed differentially in the nervous system to promote neurite growth and neuronal survival. J. Comp. Neuro1., 2008, 507(5), 1831-1845.
[44]
Han, Y.; Chen, X.; Shi, F.; Li, S.; Huang, J.; Xie, M.; Hu, L.; Hoidal, J.R.; Xu, P. CPG15, a new factor upregulated after ischemic brain injury, contributes to neuronal network re-establishment after glutamate-induced injury. J. Neurotrauma, 2007, 24(4), 722-731.
[http://dx.doi.org/10.1089/neu.2006.0174] [PMID: 17439354]
[45]
He, Y.; Yang, G.; Wang, Y.; Ren, Y.; He, X.; Zhang, X.; Fei, Z. Expression of candidate plasticity-related gene 15 is increased following traumatic brain injury. Neurol. Res., 2013, 35(2), 174-180.
[http://dx.doi.org/10.1179/1743132812Y.0000000134] [PMID: 23336599]
[46]
Wibrand, K.; Messaoudi, E.; Håvik, B.; Steenslid, V.; Løvlie, R.; Steen, V.M.; Bramham, C.R. Identification of genes co‐upregulated with Arc during BDNF‐induced long‐term potentiation in adult rat dentate gyrus in vivo. Eur. J. Neurosci., 2006, 23(6), 1501-1511.
[http://dx.doi.org/10.1111/j.1460-9568.2006.04687.x] [PMID: 16553613]
[47]
Zhang, Z.; Zhou, H.; Zhou, J. Neuritin inhibits astrogliosis to ameliorate diabetic cognitive dysfunction. J. Mol. Endocrinol., 2021, 66(4), 259-272.
[http://dx.doi.org/10.1530/JME-20-0321] [PMID: 33729996]
[48]
Xi, C.; Zhang, Y.; Yan, M.; Lv, Q.; Lu, H.; Zhou, J.; Wang, Y.; Li, J. Exogenous neuritin treatment improves survivability and functions of Schwann cells with improved outgrowth of neurons in rat diabetic neuropathy. J. Cell. Mol. Med., 2020, 24(17), 10166-10176.
[http://dx.doi.org/10.1111/jcmm.15627] [PMID: 32667138]

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