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The involvement of the mGluR5-mediated JNK signaling pathway in rats with diabetic retinopathy

  • Yan-Ni ZhuEmail author
  • Guo-Jin Zuo
  • Qi Wang
  • Xiao-Ming Chen
  • Jin-Kui Cheng
  • Shu Zhang
Original Paper

Abstract

Objective

To understand the involvement of the mGluR5-mediated JNK signaling pathway in rats with diabetic retinopathy (DR).

Methods

This study established rat models of diabetes mellitus (DM), which were divided into Normal, DM, DM + CHPG (mGluR5 agonist CHPG), and DM + MTEP (mGluR5 antagonist MTEP) groups. The blood glucose and weight of rats were recorded. EB staining was used for observation of blood–retinal barrier (BRB) damage. Neural retina function was measured by pattern electroretinogram (ERG). PAS and NG2 immunohistochemistry were conducted to evaluate the retinal vascular morphology. The TUNEL assay and active caspase-3 immunohistochemistry were performed to detect retinal cell apoptosis. Additionally, the expression levels of superoxide dismutase (SOD) and methylenedioxyamphetamine (MDA) were measured. Moreover, expression levels of mGluR5 and JNK pathway-related proteins were detected by western blot.

Results

When compared with control rats, rats in the DM group showed decreased amplitude and latency of the peak times in the ERG test; further, DM group rats presented increases in blood glucose, BRB permeability, a retinal capillary area density, retinal cell apoptosis with an increased number of active caspase-3-positive cells, MDA level, mGluR5 levels, and the ratio of p-JNK/JNK, and they showed reductions in body weight and SOD activity, as well as in the number of pericytes and in the pericyte coverage (all P < 0.05). However, rats in DM + CHPG group had stronger negative effects than those in DM group (all P < 0.05). Rats from DM + MTEP group showed an opposite trend compared with the DM rats (all P < 0.05).

Conclusion

The level of mGluR5 in DR rats was upregulated, whereas inhibition of mGluR5 alleviated retinal pathological damage and decreased cell apoptosis to improve DR via suppression of the JNK signaling pathway, which provided a scientific theoretical basis for the clinical treatment of DR.

Keywords

mGluR5 JNK signaling pathway Diabetes mellitus Diabetic retinopathy Apoptosis 

Notes

Acknowledgements

The authors appreciate the reviewers for their useful comments in this paper.

Compliance with ethical standards

Conflict of interest

No potential conflicts of interest were disclosed.

Ethical approval

The animal experimental design used in this study was approved by the Experimental Animal Ethics Committee of the First People’s Hospital of Jingzhou; all experimental animal behaviors strictly followed the laboratory animal management and operation guide issued by the National Institutes of Health.

References

  1. 1.
    El-Asrar AM (2012) Role of inflammation in the pathogenesis of diabetic retinopathy. Middle East Afr J Ophthalmol 19:70–74CrossRefPubMedGoogle Scholar
  2. 2.
    Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW et al (2012) Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 35:556–564CrossRefPubMedGoogle Scholar
  3. 3.
    Huang H, He J, Johnson D, Wei Y, Liu Y et al (2015) Deletion of placental growth factor prevents diabetic retinopathy and is associated with Akt activation and HIF1α-VEGF pathway inhibition. Diabetes 64:200–212CrossRefPubMedGoogle Scholar
  4. 4.
    Saxena R, Singh D, Saklani R, Gupta SK (2016) Clinical biomarkers and molecular basis for optimized treatment of diabetic retinopathy: current status and future prospects. Eye Brain 8:1–13CrossRefPubMedGoogle Scholar
  5. 5.
    Wen D, Song W, Liu S, Tan X, Liu F (2015) Upregulated expression of N-methyl-D-aspartate receptor 1 and nitric oxide synthase during form-deprivation myopia in guinea pigs. Int J Clin Exp Pathol 8:3819–3826PubMedGoogle Scholar
  6. 6.
    Ji M, Miao Y, Dong LD, Chen J, Mo XF et al (2012) Group I mGluR-mediated inhibition of Kir channels contributes to retinal Muller cell gliosis in a rat chronic ocular hypertension model. J Neurosci 32:12744–12755CrossRefPubMedGoogle Scholar
  7. 7.
    Alexander GM, Godwin DW (2006) Metabotropic glutamate receptors as a strategic target for the treatment of epilepsy. Epilepsy Res 71:1–22CrossRefPubMedGoogle Scholar
  8. 8.
    Gerber U, Gee CE, Benquet P (2007) Metabotropic glutamate receptors: intracellular signaling pathways. Curr Opin Pharmacol 7:56–61CrossRefPubMedGoogle Scholar
  9. 9.
    Gao F, Li F, Miao Y, Dong LD, Zhang SH et al (2015) Group I metabotropic glutamate receptor agonist DHPG modulates Kir4.1 protein and mRNA in cultured rat retinal Muller cells. Neurosci Lett 588:12–17CrossRefPubMedGoogle Scholar
  10. 10.
    Yang L, Mao L, Chen H, Catavsan M, Kozinn J et al (2006) A signaling mechanism from Gαq-protein-coupled metabotropic glutamate receptors to gene expression: role of the c-Jun N-terminal kinase pathway. J Neurosci 26:971–980CrossRefPubMedGoogle Scholar
  11. 11.
    Wagner EF, Nebreda AR (2009) Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer 9:537–549CrossRefPubMedGoogle Scholar
  12. 12.
    Chen F (2012) JNK-induced apoptosis, compensatory growth, and cancer stem cells. Cancer Res 72:379–386CrossRefPubMedGoogle Scholar
  13. 13.
    Dhanasekaran DN, Reddy EP (2008) JNK signaling in apoptosis. Oncogene 27:6245–6251CrossRefPubMedGoogle Scholar
  14. 14.
    Bayne K (1996) Revised guide for the care and use of laboratory animals available. American Physiological Society. Physiologist 39(199):111–208Google Scholar
  15. 15.
    Zheng Z, Chen H, Ke G, Fan Y, Zou H et al (2009) Protective effect of perindopril on diabetic retinopathy is associated with decreased vascular endothelial growth factor-to-pigment epithelium-derived factor ratio: involvement of a mitochondria-reactive oxygen species pathway. Diabetes 58:954–964CrossRefPubMedGoogle Scholar
  16. 16.
    Yang H, Liu R, Cui Z, Chen ZQ, Yan S et al (2011) Functional characterization of 58-kilodalton inhibitor of protein kinase in protecting against diabetic retinopathy via the endoplasmic reticulum stress pathway. Mol Vis 17:78–84PubMedGoogle Scholar
  17. 17.
    Shi X, Liao S, Mi H, Guo C, Qi D et al (2012) Hesperidin prevents retinal and plasma abnormalities in streptozotocin-induced diabetic rats. Molecules 17:12868–12881CrossRefPubMedGoogle Scholar
  18. 18.
    Chen W, Yao X, Zhou C, Zhang Z, Gui G et al (2017) Danhong huayu koufuye prevents diabetic retinopathy in streptozotocin-induced diabetic rats via antioxidation and anti-inflammation. Mediat Inflamm 2017:3059763Google Scholar
  19. 19.
    Rao VR, Prescott E, Shelke NB, Trivedi R, Thomas P et al (2010) Delivery of SAR 1118 to the retina via ophthalmic drops and its effectiveness in a rat streptozotocin (STZ) model of diabetic retinopathy (DR). Invest Ophthalmol Vis Sci 51:5198–5204CrossRefPubMedGoogle Scholar
  20. 20.
    Liu N, Zhao N, Chen L, Cai N (2015) Survivin contributes to the progression of diabetic retinopathy through HIF-1α pathway. Int J Clin Exp Pathol 8:9161–9167PubMedGoogle Scholar
  21. 21.
    Mandarino LJ, Sundarraj N, Finlayson J, Hassell HR (1993) Regulation of fibronectin and laminin synthesis by retinal capillary endothelial cells and pericytes in vitro. Exp Eye Res 57:609–621CrossRefPubMedGoogle Scholar
  22. 22.
    Choi JA, Chung YR, Byun HR, Park H, Koh JY et al (2017) The anti-ALS drug riluzole attenuates pericyte loss in the diabetic retinopathy of streptozotocin-treated mice. Toxicol Appl Pharmacol 315:80–89CrossRefPubMedGoogle Scholar
  23. 23.
    Hammes HP (2005) Pericytes and the pathogenesis of diabetic retinopathy. Horm Metab Res 37(Suppl 1):39–43CrossRefPubMedGoogle Scholar
  24. 24.
    Frank RN (2002) Potential new medical therapies for diabetic retinopathy: protein kinase C inhibitors. Am J Ophthalmol 133:693–698CrossRefPubMedGoogle Scholar
  25. 25.
    Wisniewska-Kruk J, Klaassen I, Vogels IM, Magno AL, Lai CM et al (2014) Molecular analysis of blood-retinal barrier loss in the Akimba mouse, a model of advanced diabetic retinopathy. Exp Eye Res 122:123–131CrossRefPubMedGoogle Scholar
  26. 26.
    Park SW, Yun JH, Kim JH, Kim KW, Cho CH et al (2014) Angiopoietin 2 induces pericyte apoptosis via α3β1 integrin signaling in diabetic retinopathy. Diabetes 63:3057–3068CrossRefPubMedGoogle Scholar
  27. 27.
    Um JW, Kaufman AC, Kostylev M, Heiss JK, Stagi M et al (2013) Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein. Neuron 79:887–902CrossRefPubMedGoogle Scholar
  28. 28.
    Xia N, Zhang Q, Wang ST, Gu L, Yang HM et al (2015) Blockade of metabotropic glutamate receptor 5 protects against DNA damage in a rotenone-induced Parkinson’s disease model. Free Radic Biol Med 89:567–580CrossRefPubMedGoogle Scholar
  29. 29.
    Schori H, Kipnis J, Yoles E, WoldeMussie E, Ruiz G et al (2001) Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: implications for glaucoma. Proc Natl Acad Sci USA 98:3398–3403CrossRefPubMedGoogle Scholar
  30. 30.
    Chen K, Zhang Q, Wang J, Liu F, Mi M et al (2009) Taurine protects transformed rat retinal ganglion cells from hypoxia-induced apoptosis by preventing mitochondrial dysfunction. Brain Res 1279:131–138CrossRefPubMedGoogle Scholar
  31. 31.
    Behl Y, Krothapalli P, Desta T, DiPiazza A, Roy S et al (2008) Diabetes-enhanced tumor necrosis factor-α production promotes apoptosis and the loss of retinal microvascular cells in type 1 and type 2 models of diabetic retinopathy. Am J Pathol 172:1411–1418CrossRefPubMedGoogle Scholar
  32. 32.
    Geraldes P, Hiraoka-Yamamoto J, Matsumoto M, Clermont A, Leitges M et al (2009) Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nat Med 15:1298–1306CrossRefPubMedGoogle Scholar
  33. 33.
    Deng G, Moran EP, Cheng R, Matlock G, Zhou K et al (2017) Therapeutic effects of a novel agonist of peroxisome proliferator-activated receptor alpha for the treatment of diabetic retinopathy. Invest Ophthalmol Vis Sci 58:5030–5042CrossRefPubMedGoogle Scholar
  34. 34.
    Park SH, Park JW, Park SJ, Kim KY, Chung JW et al (2003) Apoptotic death of photoreceptors in the streptozotocin-induced diabetic rat retina. Diabetologia 46:1260–1268CrossRefPubMedGoogle Scholar
  35. 35.
    Barcelona PF, Sitaras N, Galan A, Esquiva G, Jmaeff S et al (2016) p75NTR and its ligand ProNGF activate paracrine mechanisms etiological to the vascular, inflammatory, and neurodegenerative pathologies of diabetic retinopathy. J Neurosci 36:8826–8841CrossRefPubMedGoogle Scholar
  36. 36.
    Shen W, Fruttiger M, Zhu L, Chung SH, Barnett NL et al (2012) Conditional Mullercell ablation causes independent neuronal and vascular pathologies in a novel transgenic model. J Neurosci 32:15715–15727CrossRefPubMedGoogle Scholar
  37. 37.
    Zhou CH, Zhang MX, Zhou SS, Li H, Gao J et al (2017) SIRT1 attenuates neuropathic pain by epigenetic regulation of mGluR1/5 expressions in type 2 diabetic rats. Pain 158:130–139CrossRefPubMedGoogle Scholar
  38. 38.
    Zhang H, Li Q, Graham RK, Slow E, Hayden MR et al (2008) Full length mutant huntingtin is required for altered Ca2+ signaling and apoptosis of striatal neurons in the YAC mouse model of Huntington’s disease. Neurobiol Dis 31:80–88CrossRefPubMedGoogle Scholar
  39. 39.
    Zhao Y, Li Q, Li XY, Cui P, Gao F et al (2018) Involvement of mGluR I in EphB/ephrinB reverse signaling activation induced retinal ganglion cell apoptosis in a rat chronic hypertension model. Brain Res 1683:27–35CrossRefPubMedGoogle Scholar
  40. 40.
    Lin BQ, Zhou JY, Ma Y, Deng YJ, Zheng CJ et al (2011) Preventive effect of danhong huayu koufuye on diabetic retinopathy in rats. Int J Ophthalmol 4:599–604PubMedGoogle Scholar
  41. 41.
    Dede AD, Tournis S, Dontas I, Trovas G (2014) Type 2 diabetes mellitus and fracture risk. Metabolism 63:1480–1490CrossRefPubMedGoogle Scholar
  42. 42.
    Huang XP, Qiu YY, Wang B, Ding H, Tang YH et al (2014) Effects of Astragaloside IV combined with the active components of Panax notoginseng on oxidative stress injury and nuclear factor-erythroid 2-related factor 2/heme oxygenase-1 signaling pathway after cerebral ischemia-reperfusion in mice. Pharmacogn Mag 10:402–409CrossRefPubMedGoogle Scholar
  43. 43.
    El Mesallamy HO, Metwally NS, Soliman MS, Ahmed KA, Abdel Moaty MM (2011) The chemopreventive effect of Ginkgo biloba and Silybum marianum extracts on hepatocarcinogenesis in rats. Cancer Cell Int 11:38CrossRefPubMedGoogle Scholar
  44. 44.
    Tezel G, Chauhan BC, LeBlanc RP, Wax MB (2003) Immunohistochemical assessment of the glial mitogen-activated protein kinase activation in glaucoma. Invest Ophthalmol Vis Sci 44:3025–3033CrossRefPubMedGoogle Scholar
  45. 45.
    Yang W, Tiffany-Castiglioni E, Koh HC, Son IH (2009) Paraquat activates the IRE1/ASK1/JNK cascade associated with apoptosis in human neuroblastoma SH-SY5Y cells. Toxicol Lett 191:203–210CrossRefPubMedGoogle Scholar
  46. 46.
    Li X, Weng H, Xu C, Reece EA, Yang P (2012) Oxidative stress-induced JNK1/2 activation triggers proapoptotic signaling and apoptosis that leads to diabetic embryopathy. Diabetes 61:2084–2092CrossRefPubMedGoogle Scholar
  47. 47.
    Zhao L, Jiao Q, Chen X, Yang P, Zhao B et al (2012) mGluR5 is involved in proliferation of rat neural progenitor cells exposed to hypoxia with activation of mitogen-activated protein kinase signaling pathway. J Neurosci Res 90:447–460CrossRefPubMedGoogle Scholar
  48. 48.
    Fukuda K, Tesch GH, Nikolic-Paterson DJ (2008) c-Jun amino terminal kinase 1 deficient mice are protected from streptozotocin-induced islet injury. Biochem Biophys Res Commun 366:710–716CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Yan-Ni Zhu
    • 1
    Email author
  • Guo-Jin Zuo
    • 1
  • Qi Wang
    • 1
  • Xiao-Ming Chen
    • 1
  • Jin-Kui Cheng
    • 1
  • Shu Zhang
    • 1
  1. 1.Department of OphthalmologyJingzhou First People’s HospitalJingzhou, HubeiChina

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