Effect of receptor protein kinase inhibition on the morphogenesis of experimental diabetic retinopathy

Authors

DOI:

https://doi.org/10.31288/oftalmolzh202514753

Keywords:

diabetic retinopathy, streptozotocin, microaneurysms, retinal degeneration, gliosis, insulin

Abstract

Purpose: To assess the effect of receptor protein kinase inhibition with the multi-target kinase inhibitor sorafenib on the morphogenesis of experimental diabetic retinopathy (DR).
Material and Methods: Type 1 diabetes mellitus (DM) was induced in 60 Wistar male rats (age, 3 months) by single intraperitoneal injection of streptozotocin (STZ; Sigma-Aldrich, China) at a dose of 50 mg/kg body weight. Rats were divided into 3 groups 20 rats each: group 1 or controls (no treatment), group 2 (30 units of insulin only (Novo Nordisk A/S, Bagsvaerd, Denmark) every other day), and group 3 (insulin combined with soranib (sorafenib, Сipla, India), 50 µg/kg body weight daily). Five intact rats were used to determine baseline parameters. Rats were euthanized on days 7, 14, 28 and month 3. Paraffin retinal sections were stained with hematoxylin and eosin or AZAN trichrome (BIOGNOST Ltd, Croatia) and visualized by light microscopy.
Results: On day 7 after STZ injection, general signs of diabetic damage to the retina (vascular abnormalities, retinal edema and ischemic areas) were observed. Specific signs of DR (microaneurysms along the inner retinal surface, ganglion cell degeneration, reactive gliosis, cell proliferation in the outer retinal layers and an increased inner limiting membrane thickness with accumulation of coarse basophilic fibers) manifested subsequently in the course of experimental type 1 DM. Insulin-only treatment contributed to a reduction in all manifestations of diabetic damage to the retina, whereas application of sorafenib as an adjunct to treatment reduced general signs and prevented specific manifestations of DR.
Conclusion: Inhibition of cellular protein kinases made it possible to prevent signs of DR, which prompts further research on opportunities for application of this approach in the treatment of DR.

References

Wong TY, Sabanayagam C. Strategies to Tackle the Global Burden of Diabetic Retinopathy: From Epidemiology to Artificial Intelligence. Ophthalmologica. 2020;243(1):9-20. https://doi.org/10.1159/000502387

Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, Stein C, Basit A, Chan JCN, Mbanya JC, Pavkov ME, Ramachandaran A, Wild SH, James S, Herman WH, Zhang P, Bommer C, Kuo S, Boyko EJ, Magliano DJ. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022 Jan;183:109119. https://doi.org/10.1016/j.diabres.2021.109119

Himasa FI, Singhal M, Ojha A, Kumar B. Prospective for Diagnosis and Treatment of Diabetic Retinopathy. Curr Pharm Des. 2022;28(7):560-569. https://doi.org/10.2174/1381612827666211115154907

Kang Q, Yang C. Oxidative stress and diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications. Redox Biol. 2020 Oct;37:101799. https://doi.org/10.1016/j.redox.2020.101799

Mrugacz M, Bryl A, Zorena K. Retinal Vascular Endothelial Cell Dysfunction and Neuroretinal Degeneration in Diabetic Patients. J Clin Med. 2021 Jan 25;10(3):458. https://doi.org/10.3390/jcm10030458

Striglia E, Caccioppo A, Castellino N, Reibaldi M, Porta M. Emerging drugs for the treatment of diabetic retinopathy. Expert OpinEmerg Drugs. 2020 Sep;25(3):261-271. https://doi.org/10.1080/14728214.2020.1801631

Ziablitsev SV, Vodianyk VV, Diadyk OO. [Effect of tyrosine kinase inhibition on the expression of vascular endothelial growth factor and development of diabetic retinopathy]. Fiziologichnyi zhurnal. 2023; 69(5):22-32. Ukrainian. https://doi.org/10.15407/fz69.05.22

Ziablitsev SV, Vodianyk VV. Retinal apoptosis and the effect of tyrosine kinase inhibition in experimental diabetes. 2023;5(514):34-40. https://doi.org/10.31288/oftalmolzh202353440

Ziablitsev SV, Usenko KO, Dobrovynska OV, Perepelytsia IV, Andrushchenko VA. [Effect of tyrosine protein kinase inhibition on metabolism in experimental diabetes]. Fiziologichnyi zhurnal. 2024;3(70):16-26. https://doi.org/10.15407/fz70.03.016

MaJ, SuiF, LiuY, YuanM, DangH, LiuR, ShiB, HouP. Sorafenib decreases glycemia by impairing hepatic glucose metabolism. Endocrine. 2022 Dec;78(3):446-457. https://doi.org/10.1007/s12020-022-03202-9

Guo S, Zhang C, Zeng H, Xia Y, Weng C, Deng Y, Wang L, Wang H. Glycolysis maintains AMPK activation in sorafenib-induced Warburg effect. Mol Metab. 2023 Nov;77:101796. https://doi.org/10.1016/j.molmet.2023.101796

Jian C, Fu J, Cheng X, Shen LJ, Ji YX, Wang X, Pan S, Tian H, etal. Low-dose sorafenib acts as a mitochondrial uncoupler and ameliorates non-alcoholics tea to hepatitis. Cell Metab. 2020 May 5;31(5):892-908.e11. https://doi.org/10.1016/j.cmet.2020.04.011

Beckers P, Müller C, Wallnisch C, Bartolomaeus T. Getting two birds with one stone: Combining immunohistochemistry and Azan staining in animal morphology. J BiolMethods. 2021 Sep 3;8(3):e153. https://doi.org/10.14440/jbm.2021.354

Wang W, Lo ACY. Diabetic Retinopathy: Pathophysiology and Treatments. Int J Mol Sci. 2018 Jun 20;19(6):1816. https://doi.org/10.3390/ijms19061816

Newman EA. Functional hyperemia and mechanisms of neurovascular coupling in the retinal vasculature. J Cereb Blood Flow Metab. 2013 Nov;33(11):1685-95. https://doi.org/10.1038/jcbfm.2013.145

Arboleda-Velasquez JF, Valdez CN, Marko CK, D'Amore PA. From pathobiology to the targeting of pericytes for the treatment of diabetic retinopathy. Curr Diab Rep. 2015 Feb;15(2):573. https://doi.org/10.1007/s11892-014-0573-2

Ren J, Zhang S, Pan Y, Jin M, Li J, Luo Y, Sun X, Li G. Diabetic retinopathy: Involved cells, biomarkers, and treatments. Front Pharmacol. 2022 Aug 9;13:953691. https://doi.org/10.3389/fphar.2022.953691

Wu D, Kanda A, Liu Y, Noda K, Murata M, Ishida S. Involvement of Müller Glial Autoinduction of TGF-β in Diabetic Fibrovascular Proliferation Via Glial-Mesenchymal Transition. Invest Ophthalmol Vis Sci. 2020 Dec 1;61(14):29. https://doi.org/10.1167/iovs.61.14.29

Mohammad G, Kowluru RA. Diabetic retinopathy and signaling mechanism for activation of matrix metalloproteinase-9. J Cell Physiol. 2012 Mar;227(3):1052-61. https://doi.org/10.1002/jcp.22822

Wu C, Xu K, Liu W, Liu A, Liang H, Li Q, Feng Z, Yang Y, Ding J, Zhang T, Liu Y, Liu X, Zuo Z. Protective Effect of Raf-1 Kinase Inhibitory Protein on Diabetic Retinal Neurodegeneration through P38-MAPK Pathway. Curr Eye Res. 2022 Jan;47(1):135-142. https://doi.org/10.1080/02713683.2021.1944644

Abdelgalil AA, Alkahtani HM, Al-Jenoobi FI. Sorafenib. Profiles Drug Subst Excip Relat Methodol. 2019;44:239-266. https://doi.org/10.1016/bs.podrm.2018.11.003

Juan LW, En LM, Hao L, Kai HY, Ju H. Sorafenib regulating ERK signals pathway in gastric cancer cell. EnvironToxicol Pharmacol. 2014 Sep;38(2):438-43. https://doi.org/10.1016/j.etap.2014.07.012

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2025-03-03

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1.
Usenko KO. Effect of receptor protein kinase inhibition on the morphogenesis of experimental diabetic retinopathy. J.ophthalmol. (Ukraine) [Internet]. 2025 Mar. 3 [cited 2025 Mar. 9];(1):47-53. Available from: http://ua.ozhurnal.com/index.php/files/article/view/223

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No. 1 (2025): Journal of Ophthalmology (Ukraine)

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Experimental Studies

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Copyright (c) 2025 Usenko K.O.

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