Skip to main content

Advertisement

Log in

MicroRNA-301a-3p promotes diabetic retinopathy via regulation of six-transmembrane epithelial antigen of prostate 4

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective and design

Diabetic retinopathy (DR) is one of the most serious microvascular complications of diabetes mellitus (DM). MicroRNAs (miRNAs) have been discovered to play a crucial role in DR, but the mechanisms underlying the effects of miR-301a-3p on DR are poorly understood. This paper was designed to explore the possible role of miR-301a-3p in DR.

Methods

The diabetic rat model was established by a single intraperitoneal injection of streptozotocin (STZ). The effects of miR-301a-3p on the biological functions of HRECs were determined through a series of experiments in vitro/vivo.

Results

The results revealed that interference with miR-301a-3p could decrease the expressions of inflammatory factors and apoptosis in the retinal tissue of DR. Furthermore, it can alleviate the oxidative stress in DR serum, reduce VEGF expression, increase endothelial cell marker expression, and inhibit (High Glucose) HG-induced apoptosis of HRECs. Six-transmembrane epithelial antigen of prostate 4 (STEAP4) was the target of miR-301a-3p. All the effects of miR-301a-3p in DR model were reversed by STEAP4 inhibitor.

Conclusion

miR-301a-3p promotes diabetic retinopathy via regulation of STEAP4. The findings in this study may provide a vital reference for the drug research and development in DR treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med. 2012;366:1227–39.

    Article  CAS  Google Scholar 

  2. Burnett A, Lee L, D’Esposito F, Wabulembo G, Cama A, Guldan G, et al. Rapid assessment of avoidable blindness and diabetic retinopathy in people aged 50 years and older in the National Capital District of Papua New Guinea. Br J Ophthalmol. 2019;103:743–7.

    Article  Google Scholar 

  3. Shin ES, Sorenson CM, Sheibani N. Diabetes and retinal vascular dysfunction. J Ophthalmic Vis Res. 2014;9:362–73.

    PubMed  PubMed Central  Google Scholar 

  4. Mao JB, Wu HF, Chen YQ, Zhao SX, Tao JW, Zhang Y, et al. Effect of intravitreal conbercept treatment before vitrectomy in proliferative diabetic retinopathy. Int J Ophthalmol. 2018;11:1217–21.

    PubMed  PubMed Central  Google Scholar 

  5. Xu ZH, Gao YY, Zhang HT, Ruan KF, Feng Y. Progress in experimental and clinical research of the diabetic retinopathy treatment using traditional Chinese medicine. Am J Chin Med. 2018;4:1–27.

    Google Scholar 

  6. Gong Q, Xie J, Liu Y, Li Y, Su G. Differentially expressed MicroRNAs in the development of early diabetic retinopathy. J Diabetes Res. 2017;7:4727942.

    Google Scholar 

  7. Zhuang P, Muraleedharan CK, Xu S. Intraocular delivery of miR-146 inhibits diabetes-induced retinal functional defects in diabetic rat model. Invest Ophthalmol Vis Sci. 2017;58:1646–55.

    Article  CAS  Google Scholar 

  8. Kovacs B, Lumayag S, Cowan C, Xu S. MicroRNAs in early diabetic retinopathy in streptozotocin-induced diabetic rats. Invest Ophthalmol Vis Sci. 2011;52:4402–9.

    Article  CAS  Google Scholar 

  9. Ye EA, Steinle JJ. miR-146a attenuates inflammatory pathways mediated by TLR4/NF-kappaB and TNFalpha to protect primary human retinal microvascular endothelial cells grown in high glucose. Med Inflamm. 2016;2016:3958453.

    Google Scholar 

  10. McArthur K, Feng B, Wu Y, Chen S, Chakrabarti S. MicroRNA-200b regulates vascular endothelial growth factor-mediated alterations in diabetic retinopathy. Diabetes. 2011;60:1314–23.

    Article  CAS  Google Scholar 

  11. Liu TT, Hao Q, Zhang Y, Li ZH, Cui ZH, Yang W. Effects of microRNA-133b on retinal vascular endothelial cell proliferation and apoptosis through angiotensinogen-mediated angiotensin II- extracellular signal-regulated kinase 1/2 signalling pathway in rats with diabetic retinopathy. Acta Ophthalmol. 2018;96:e626–35.

    Article  CAS  Google Scholar 

  12. Lettlova S, Brynychova V, Blecha J, Vrana D, Vondrusova M, Soucek P, et al. MiR-301a-3p suppresses estrogen signaling by directly inhibiting ESR1 in ERalpha positive breast cancer. Cell Physiol Biochem. 2018;46:2601–15.

    Article  CAS  Google Scholar 

  13. Dong Y, Wang J, Du K, Jia T, Zhang Y, Song J, et al. MiR-301a-3p in the pathogenesis of bacterial meningitis by targeting Cx43. NeuroReport. 2019;30:174–81.

    Article  CAS  Google Scholar 

  14. Xia X, Zhang K, Cen G, Jiang T, Cao J, Huang K, et al. MicroRNA-301a-3p promotes pancreatic cancer progression via negative regulation of SMAD4. Oncotarget. 2015;6:21046–63.

    Article  Google Scholar 

  15. Xia X, Zhang K, Luo G, Cen G, Cao J, Huang K, et al. Downregulation of miR-301a-3p sensitizes pancreatic cancer cells to gemcitabine treatment via PTEN. Am J Transl Res. 2017;9:1886–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Ozmen F, Ozmen MM, Gelecek S, Bilgic I, Moran M, Sahin TT. STEAP4 and HIF-1alpha gene expressions in visceral and subcutaneous adipose tissue of the morbidly obese patients. Mol Immunol. 2016;73:53–9.

    Article  CAS  Google Scholar 

  17. Xu HM, Cui YZ, Wang WG, Cheng HX, Sun YJ, Zhao HY, et al. Expression and clinical significance of obesity-associated gene STEAP4 in obese children. Genet Mol Res. 2016;1:15.

    Google Scholar 

  18. Yoo SK, Cheong J, Kim HY. STAMPing into mitochondria. Int J Biol Sci. 2014;10:321–6.

    Article  Google Scholar 

  19. Gomes IM, Maia CJ, Santos CR. STEAP proteins: from structure to applications in cancer therapy. Mol Cancer Res. 2012;10:573–87.

    Article  CAS  Google Scholar 

  20. Korkmaz CG, Korkmaz KS, Kurys P, Elbi C, Wang L, Klokk TI, et al. Molecular cloning and characterization of STAMP2, an androgen-regulated six transmembrane protein that is overexpressed in prostate cancer. Oncogene. 2005;24:4934–45.

    Article  CAS  Google Scholar 

  21. Jung DH, Kim YS, Kim NH, Lee J, Jang DS, Kim JS. Extract of Cassiae Semen and its major compound inhibit S100b-induced TGF-beta1 and fibronectin expression in mouse glomerular mesangial cells. Eur J Pharmacol. 2010;641:7–14.

    Article  CAS  Google Scholar 

  22. Wang J, Han L, Wang ZH, Ding WY, Shang YY, Tang MX, et al. Overexpression of STAMP2 suppresses atherosclerosis and stabilizes plaques in diabetic mice. J Cell Mol Med. 2014;18:735–48.

    Article  CAS  Google Scholar 

  23. Xia F, Sun JJ, Jiang YQ, Li CF. MicroRNA-384-3p inhibits retinal neovascularization through targeting hexokinase 2 in mice with diabetic retinopathy. J Cell Physiol. 2018;234:721–30.

    Article  Google Scholar 

  24. Nakao S, Yoshida S, Kaizu Y, Yamaguchi M, Wada I, Ishibashi T, et al. Microaneurysm detection in diabetic retinopathy using OCT angiography may depend on intramicroaneurysmal turbulence. Ophthalmol Retina. 2018;2:1171–3.

    Article  Google Scholar 

  25. LeBlanc ME, Wang W, Chen X, Caberoy NB, Guo F, Shen C, et al. Secretogranin III as a disease-associated ligand for antiangiogenic therapy of diabetic retinopathy. J Exp Med. 2017;214:1029–47.

    Article  CAS  Google Scholar 

  26. Prunty MC, Aung MH, Hanif AM, Allen RS, Chrenek MA, Boatright JH, et al. In vivo imaging of retinal oxidative stress using a reactive oxygen species-activated fluorescent probe. Invest Ophthalmol Vis Sci. 2015;56:5862–70.

    Article  CAS  Google Scholar 

  27. Sasongko MB, Wong TY, Jenkins AJ, Nguyen TT, Shaw JE, Wang JJ. Circulating markers of inflammation and endothelial function, and their relationship to diabetic retinopathy. Diabet Med. 2015;32:686–91.

    Article  CAS  Google Scholar 

  28. Panguluri SK, Tur J, Chapalamadugu KC, Katnik C, Cuevas J, Tipparaju SM. MicroRNA-301a mediated regulation of Kv4.2 in diabetes: identification of key modulators. PLoS ONE. 2013;8:e60545.

    Article  CAS  Google Scholar 

  29. Behl T, Kotwani A. Exploring the various aspects of the pathological role of vascular endothelial growth factor (VEGF) in diabetic retinopathy. Pharmacol Res. 2015;99:137–48.

    Article  CAS  Google Scholar 

  30. Qaum T, Xu Q, Joussen AM, Clemens MW, Qin W, Miyamoto K, et al. VEGF-initiated blood-retinal barrier breakdown in early diabetes. Invest Ophthalmol Vis Sci. 2001;42:2408–13.

    CAS  PubMed  Google Scholar 

  31. Sun N, Ning B, Hansson KM, Bruce AC, Seaman SA, Zhang C, et al. Modified VEGF-A mRNA induces sustained multifaceted microvascular response and accelerates diabetic wound healing. Sci Rep. 2018;8:17509.

    Article  Google Scholar 

  32. Li R, Qi Y, Jiang M, Zhang T, Wang H, Wang L, et al. Primary tumor-secreted VEGF induces vascular hyperpermeability in premetastatic lung via the occludin phosphorylation/ubiquitination pathway. Mol Carcinog. 2019;2:10–30.

    Google Scholar 

  33. Spoerri PE, Afzal A, Li Calzi S, Shaw LC, Cai J, Pan H, et al. Effects of VEGFR-1, VEGFR-2, and IGF-IR hammerhead ribozymes on glucose-mediated tight junction expression in cultured human retinal endothelial cells. Mol Vis. 2006;12:32–42.

    CAS  PubMed  Google Scholar 

  34. Alacam H, Akgun S, Akca H, Ozturk O, Kabukcu BB, Herken H. miR-181b-5p, miR-195-5p and miR-301a-3p are related with treatment resistance in schizophrenia. Psychiatry Res. 2016;245:200–6.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Not applicable.

Author information

Authors and Affiliations

Authors

Contributions

YMW, LJG, and ZLL designed the study and collected the data; XYM, YMW, and LJG participated in analyzing and interpreting the data and were major contributors in writing the manuscript; ZLL critically revised the article. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Zhili Li.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interests.

Ethics approval

All animals are received the human care and experimental procedures. All experimental operations performed on all rats were subject to approved by the Ministry of Health of the People’s Republic of China (documentation number 19890503) and Animal Experiment Ethics Committee of Hebei University of Chinese Medicine. Measures were taken to minimize animal suffering.

Consent for publication

Not applicable.

Additional information

Responsible Editor: John Di Battista.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Y., Gao, L., Li, Z. et al. MicroRNA-301a-3p promotes diabetic retinopathy via regulation of six-transmembrane epithelial antigen of prostate 4. Inflamm. Res. 70, 445–457 (2021). https://doi.org/10.1007/s00011-020-01431-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-020-01431-0

Keywords

Navigation