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MicroRNA-93-5p participates in type 2 diabetic retinopathy through targeting Sirt1

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Abstract

Objective

To investigate the role of miR-93-5p in rats with type 2 diabetic retinopathy (DR) through targeting Sirt1.

Methods

The targeting correlation between miR-93-5p and Sirt1 was validated by dual-luciferase reporter gene assay. Type 2 diabetes mellitus (T2DM) rat models were received intravitreal injection of antagomir NC (negative control), miR-93-5p antagomir, miR-93-5p agomir and/or recombinant Sirt1, followed by observation of pathological changes in retina via HE staining. Besides, retinal vascular permeability was determined by fluorescein isothiocyanate-bovine serum albumin (FITC-BSA), while the retinal vasculature was observed through retinal trypsin digestion. Expression of miR-93-5p and Sirt1 was measured by qRT-PCR and Western blotting, while the levels of VEGF, proinflammatory cytokines and anti-oxidative indicators were determined using corresponding kits.

Results

MiR-93-5p could target Sirt1 as analyzed by the luciferase reporter gene assay. Rats in the T2DM group presented the up-regulation of miR-93-5p and down-regulation of Sirt1 in the retina, and miR-93-5p inhibition could up-regulate Sirt1 expression in the T2DM rats. Recombinant Sirt1 decreased retinal vascular permeability and acellular capillaries with improved pathological changes in retina from T2DM rats, which was abolished by miR-93-5p agomir. Moreover, miR-93-5p inhibition or Sirt1 overexpression decreased the levels of VEGF and proinflammatory cytokines while enhancing the activity of anti-oxidative indicators. However, indicators above had no significant differences between T2DM group and T2DM + agomir + Sirt1 group.

Conclusion

MiR-93-5p, via targeting Sirt1, could affect the vascular permeability and acellular capillaries and mitigate the inflammation and oxidative stress in the retinas, which may play a critical role in DR.

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References

  1. Maghbooli Z, Emamgholipour S, Aliakbar S, Amini M, Gorgani-Firuzjaee S, Hossein-Nezhad A (2020) Differential expressions of SIRT1, SIRT3, and SIRT4 in peripheral blood mononuclear cells from patients with type 2 diabetic retinopathy. Arch Physiol Biochem 126(4):363–368. https://doi.org/10.1080/13813455.2018.1543328

    Article  CAS  PubMed  Google Scholar 

  2. Alves MFA, Barreto FKA, Vasconcelos MA, Nascimento Neto LGD, Carneiro RF, Silva LTD et al (2020) Antihyperglycemic and antioxidant activities of a lectin from the marine red algae, Bryothamnion seaforthii, in rats with streptozotocin-induced diabetes. Int J Biol Macromol 158:773–780. https://doi.org/10.1016/j.ijbiomac.2020.04.238

    Article  CAS  PubMed  Google Scholar 

  3. Dong W, Wan EYF, Fong DYT, Kwok RLP, Chao DVK, Tan KCB et al (2020) Prediction models and nomograms for 10-year risk of end-stage renal disease in Chinese type 2 diabetes mellitus patients in primary care. Diabetes Obes Metab. https://doi.org/10.1111/dom.14292

    Article  PubMed  PubMed Central  Google Scholar 

  4. Salido EM, Bordone M, De Laurentiis A, Chianelli M, Keller Sarmiento MI, Dorfman D et al (2013) Therapeutic efficacy of melatonin in reducing retinal damage in an experimental model of early type 2 diabetes in rats. J Pineal Res 54(2):179–189. https://doi.org/10.1111/jpi.12008

    Article  CAS  PubMed  Google Scholar 

  5. Shibuya N, Kakeji Y, Shimono Y (2020) MicroRNA-93 targets WASF3 and functions as a metastasis suppressor in breast cancer. Cancer Sci 111(6):2093–2103. https://doi.org/10.1111/cas.14423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Smit-McBride Z, Nguyen AT, Yu AK, Modjtahedi SP, Hunter AA, Rashid S et al (2020) Unique molecular signatures of microRNAs in ocular fluids and plasma in diabetic retinopathy. PLoS ONE 15(7):e0235541. https://doi.org/10.1371/journal.pone.0235541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Thounaojam MC, Jadeja RN, Warren M, Powell FL, Raju R, Gutsaeva D et al (2019) MicroRNA-34a (miR-34a) mediates retinal Endothelial cell Premature senescence through mitochondrial dysfunction and loss of antioxidant activities. Antioxidants (Basel). https://doi.org/10.3390/antiox8090328

    Article  Google Scholar 

  8. You ZP, Zhang YL, Li BY, Zhu XG, Shi K (2018) Bioinformatics analysis of weighted genes in diabetic retinopathy. Invest Ophthalmol Vis Sci 59(13):5558–5563. https://doi.org/10.1167/iovs.18-25515

    Article  CAS  PubMed  Google Scholar 

  9. Liu S, Patel SH, Ginestier C, Ibarra I, Martin-Trevino R, Bai S et al (2012) MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells. PLoS Genet 8(6):e1002751. https://doi.org/10.1371/journal.pgen.1002751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mammadzada P, Bayle J, Gudmundsson J, Kvanta A, Andre H (2019) Identification of diagnostic and prognostic microRNAs for recurrent vitreous hemorrhage in patients with proliferative diabetic retinopathy. J clin med. https://doi.org/10.3390/jcm8122217

    Article  PubMed  PubMed Central  Google Scholar 

  11. Hirota K, Keino H, Inoue M, Ishida H, Hirakata A (2015). Comparisons of microRNA expression profiles in vitreous humor between eyes with macular hole and eyes with proliferative diabetic retinopathy. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 253(3):335–42.https://doi.org/10.1007/s00417-014-2692-5

  12. Zou HL, Wang Y, Gang Q, Zhang Y, Sun Y (2017). Plasma level of miR-93 is associated with higher risk to develop type 2 diabetic retinopathy. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 255(6):1159–66. https://doi.org/10.1007/s00417-017-3638-5

  13. Ragusa M, Caltabiano R, Russo A, Puzzo L, Avitabile T, Longo A et al (2013) MicroRNAs in vitreus humor from patients with ocular diseases. Mol Vis 19:430–440

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Hsu SD, Lin FM, Wu WY, Liang C, Huang WC, Chan WL, et al. (2011). miRTarBase: a database curates experimentally validated microRNA-target interactions. Nucleic acids research. 39(Database issue):D163–9. https://doi.org/10.1093/nar/gkq1107

  15. Mortuza R, Chen S, Feng B, Sen S, Chakrabarti S (2013) High glucose induced alteration of SIRTs in endothelial cells causes rapid aging in a p300 and FOXO regulated pathway. PLoS ONE 8(1):e54514. https://doi.org/10.1371/journal.pone.0054514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kowluru RA, Santos JM, Zhong Q (2014) Sirt1, a negative regulator of matrix metalloproteinase-9 in diabetic retinopathy. Invest Ophthalmol Vis Sci 55(9):5653–5660. https://doi.org/10.1167/iovs.14-14383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kowluru RA, Mishra M, Kumar B (2016) Diabetic retinopathy and transcriptional regulation of a small molecular weight G-Protein, Rac1. Exp Eye Res 147:72–77. https://doi.org/10.1016/j.exer.2016.04.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu X, Zhang Y, Liang H, Xu Y (2020) Overexpression of microRNA-216a-3p accelerates the inflammatory response in cardiomyocytes in Type 2 diabetes mellitus by targeting IFN-alpha2. Front Endocrinol (Lausanne). https://doi.org/10.3389/fendo.2020.522340

    Article  PubMed Central  Google Scholar 

  19. Xu LL, Gao W, Chen ZM, Shao KK, Wang YG, L LC, et al. (2020). Relationships between diabetic nephropathy and insulin resistance, inflammation, Trx, Txnip, CysC and serum complement levels. Eur Rev Med Pharmacol Sci. 24(22):11700–6. https://doi.org/10.26355/eurrev_202011_23815

  20. In: th, editor. Guide for the Care and Use of Laboratory Animals. The National Academies Collection: Reports funded by National Institutes of Health. Washington (DC) 2011.

  21. Azemi AK, Mokhtar SS, Rasool AHG (2020) Clinacanthus nutans leaves extract reverts endothelial dysfunction in Type 2 diabetes Rats by improving Protein expression of eNOS. Oxid Med Cell Longev 2020:7572892. https://doi.org/10.1155/2020/7572892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chu JX, Wang ZL, Han SY (2011) The effects of total flavonoids from buckwheat flowers and leaves on renal damage and PTP1B expression in type 2 diabetic Rats. Iran J Pharm Res 10(3):511–517

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Kim J, Kim CS, Lee YM, Jo K, Shin SD, Kim JS (2012). Methylglyoxal induces hyperpermeability of the blood-retinal barrier via the loss of tight junction proteins and the activation of matrix metalloproteinases. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 250(5):691–7. https://doi.org/10.1007/s00417-011-1912-5

  24. Abouhish H, Thounaojam MC, Jadeja RN, Gutsaeva DR, Powell FL, Khriza M et al (2020) Inhibition of HDAC6 attenuates diabetes-induced retinal redox imbalance and microangiopathy. Antioxid (Basel). https://doi.org/10.3390/antiox9070599

    Article  Google Scholar 

  25. Sorenson CM, Wang S, Gendron R, Paradis H, Sheibani N (2013) Thrombospondin-1 deficiency exacerbates the pathogenesis of diabetic retinopathy. J diabetes metab. https://doi.org/10.4172/2155-6156.S12-005

    Article  PubMed  PubMed Central  Google Scholar 

  26. Kovacs B, Lumayag S, Cowan C, Xu S (2011) MicroRNAs in early diabetic retinopathy in streptozotocin-induced diabetic rats. Investig ophthalmol vis sci 52(7):4402–4409. https://doi.org/10.1167/iovs.10-6879

    Article  CAS  Google Scholar 

  27. Platania CBM, Maisto R, Trotta MC, D’Amico M, Rossi S, Gesualdo C et al (2019) Retinal and circulating miRNA expression patterns in diabetic retinopathy: an in silico and in vivo approach. Br j pharmacol 176(13):2179–2194. https://doi.org/10.1111/bph.14665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dantas da Costa ESME, Polina ER, Crispim D, Sbruzzi RC, Lavinsky D, Mallmann F et al (2019) Plasma levels of miR-29b and miR-200b in type 2 diabetic retinopathy. J cell mole med 23(2):1280–1287. https://doi.org/10.1111/jcmm.14030

    Article  CAS  Google Scholar 

  29. Ruiz MA, Feng B, Chakrabarti S (2015) Polycomb repressive complex 2 regulates MiR-200b in retinal endothelial cells: potential relevance in diabetic retinopathy. PLoS ONE 10(4):e0123987. https://doi.org/10.1371/journal.pone.0123987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li EH, Huang QZ, Li GC, Xiang ZY, Zhang X (2017) Effects of miRNA-200b on the development of diabetic retinopathy by targeting VEGFA gene. Biosci Rep. https://doi.org/10.1042/BSR20160572

    Article  PubMed  PubMed Central  Google Scholar 

  31. Luo R, Jin H, Li L, Hu YX, Xiao F (2020) Long noncoding RNA MEG3 Inhibits apoptosis of retinal pigment epithelium cells induced by high glucose via the miR-93/Nrf2 Axis. Am J Pathol 190(9):1813–1822. https://doi.org/10.1016/j.ajpath.2020.05.008

    Article  CAS  PubMed  Google Scholar 

  32. Mohammad G, Abdelaziz GM, Siddiquei MM, Ahmad A, De Hertogh G, Abu El-Asrar AM (2019) Cross-talk between sirtuin 1 and the proinflammatory mediator high-mobility group box-1 in the regulation of blood-retinal barrier breakdown in diabetic retinopathy. Curr Eye Res 44(10):1133–1143. https://doi.org/10.1080/02713683.2019.1625406

    Article  CAS  PubMed  Google Scholar 

  33. Liu L, Jiang Y, Steinle JJ (2019) Epac1 and glycyrrhizin both inhibit HMGB1 levels to reduce diabetes-induced neuronal and vascular damage in the mouse retina. J Clin Med. https://doi.org/10.3390/jcm8060772

    Article  PubMed  PubMed Central  Google Scholar 

  34. Karbasforooshan H, Karimi G (2018) The role of SIRT1 in diabetic retinopathy. Biomed Pharmacother 97:190–194. https://doi.org/10.1016/j.biopha.2017.10.075

    Article  CAS  PubMed  Google Scholar 

  35. Ji Q, Han J, Wang L, Liu J, Dong Y, Zhu K et al (2020) MicroRNA-34a promotes apoptosis of retinal vascular endothelial cells by targeting SIRT1 in rats with diabetic retinopathy. Cell Cycle 19(21):2886–2896. https://doi.org/10.1080/15384101.2020.1827509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhou M, Luo J, Zhang H (2018) Role of sirtuin 1 in the pathogenesis of ocular disease (Review). Int J Mol Med 42(1):13–20. https://doi.org/10.3892/ijmm.2018.3623

    Article  CAS  PubMed  Google Scholar 

  37. Kim J, Lee YM, Kim CS, Sohn E, Jo K, Shin SD et al (2013) Ethyl pyruvate prevents methyglyoxal-induced retinal vascular injury in rats. J Diabetes Res 2013:460820. https://doi.org/10.1155/2013/460820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mishra M, Duraisamy AJ, Kowluru RA (2018) Sirt1: a guardian of the development of diabetic retinopathy. Diabetes 67(4):745–754. https://doi.org/10.2337/db17-0996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cao YL, Liu DJ, Zhang HG (2018). MiR-7 regulates the PI3K/AKT/VEGF pathway of retinal capillary endothelial cell and retinal pericytes in diabetic rat model through IRS-1 and inhibits cell proliferation. Eur Rev Med Pharmacol Sci. 22(14):4427–30. https://doi.org/10.26355/eurrev_201807_15493.

  40. Ling S, Birnbaum Y, Nanhwan MK, Thomas B, Bajaj M, Ye Y (2013) MicroRNA-dependent cross-talk between VEGF and HIF1alpha in the diabetic retina. Cell Signal 25(12):2840–2847. https://doi.org/10.1016/j.cellsig.2013.08.039

    Article  CAS  PubMed  Google Scholar 

  41. Lu JM, Zhang ZZ, Ma X, Fang SF, Qin XH (2020) Repression of microRNA-21 inhibits retinal vascular endothelial cell growth and angiogenesis via PTEN dependent-PI3K/Akt/VEGF signaling pathway in diabetic retinopathy. Exp Eye Res 190:107886. https://doi.org/10.1016/j.exer.2019.107886

    Article  CAS  PubMed  Google Scholar 

  42. Nishigaki A, Kido T, Kida N, Kakita-Kobayashi M, Tsubokura H, Hisamatsu Y et al (2020) Resveratrol protects mitochondrial quantity by activating SIRT1/PGC-1alpha expression during ovarian hypoxia. Reprod Med Biol 19(2):189–197. https://doi.org/10.1002/rmb2.12323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Pan Q, Gao Z, Zhu C, Peng Z, Song M, Li L (2020) Overexpression of histone deacetylase SIRT1 exerts an antiangiogenic role in diabetic retinopathy via miR-20a elevation and YAP/HIF1alpha/VEGFA depletion. Am J Physiol Endocrinol Metab 319(5):E932–E943. https://doi.org/10.1152/ajpendo.00051.2020

    Article  CAS  PubMed  Google Scholar 

  44. Sohn E, Kim J, Kim CS, Lee YM, Kim JS (2016) Extract of polygonum cuspidatum attenuates diabetic retinopathy by inhibiting the high-mobility group box-1 (HMGB1) signaling pathway in streptozotocin-induced diabetic rats. Nutrients 8(3):140. https://doi.org/10.3390/nu8030140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhang W, Liu H, Rojas M, Caldwell RW, Caldwell RB (2011) Anti-inflammatory therapy for diabetic retinopathy. Immunotherapy 3(5):609–628. https://doi.org/10.2217/imt.11.24

    Article  CAS  PubMed  Google Scholar 

  46. Blum A, Meerson A, Rohana H, Jabaly H, Nahul N, Celesh D et al (2019) MicroRNA-423 may regulate diabetic vasculopathy. Clin Exp Med 19(4):469–477. https://doi.org/10.1007/s10238-019-00573-8

    Article  CAS  PubMed  Google Scholar 

  47. He M, Long P, Yan W, Chen T, Guo L, Zhang Z et al (2018) ALDH2 attenuates early-stage STZ-induced aged diabetic rats retinas damage via Sirt1/Nrf2 pathway. Life Sci 215:227–235. https://doi.org/10.1016/j.lfs.2018.10.019

    Article  CAS  PubMed  Google Scholar 

  48. Zhang YF, Wei W, Li L, Tu G, Zhang Y, Yang J et al (2015) Sirt1 and HMGB1 regulate the age-induced pro-inflammatory cytokines in human retinal cells. Clin Lab 61(8):999–1008. https://doi.org/10.7754/clin.lab.2015.150141

    Article  CAS  PubMed  Google Scholar 

  49. Seleiman MF, Semida WM, Rady MM, Mohamed GF, Hemida KA, Alhammad BA et al (2020) Sequential application of antioxidants rectifies ion imbalance and strengthens antioxidant systems in salt-stressed cucumber. Plants (Basel). https://doi.org/10.3390/plants9121783

    Article  PubMed Central  Google Scholar 

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Acknowledgements

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

Funding

The study supported by the Key research plan of Health Commission of Hebei Province (No: 20210807).

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Authors and Affiliations

  1. Department of Ophthalmology, Shijiazhuang People’s Hospital, No. 365, Jianhua South Street, Yuhua District, Shijiazhuang, 050030, Hebei Province, China

    Hui Wang, Xian Su, Qian-Qian Zhang, Ying-Ying Zhang, Zhan-Ya Chu, Jin-Ling Zhang & Qian Ren

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  1. Hui Wang
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  2. Xian Su
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Contributions

H.W., X.S., Z.Y.C. and Q.Q.Z. contributed to development of the study designs and experimental concepts proposed in the study; Q.R. and X.S. contributed reagents/materials/analysis tools; H.W., Q.Q.Z. and Y.Y.Z. conducted experiments, including euthanasia of rats, tissue extraction, etc.; H.W. and Q.Q.Z. acquired data; Y.Y.Z. and Z.Y.C. analyzed data; J.L.Z. interpreted results of experiments; Q.Q.Z. and J.L.Z. prepared figures; X.S. and H.W. analyzed data and wrote the manuscript; H.W., X.S. and Q.R. revised manuscript; all of them approved final version of manuscript.

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Correspondence to Qian Ren.

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Wang, H., Su, X., Zhang, QQ. et al. MicroRNA-93-5p participates in type 2 diabetic retinopathy through targeting Sirt1. Int Ophthalmol 41, 3837–3848 (2021). https://doi.org/10.1007/s10792-021-01953-4

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