Changes in the amount of matrix metalloproteinases and kynurenines in individuals with diabetic retinopathy, their role in the development of the disease

Cover Page


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

INTRODUCTION: Diabetic retinopathy (DR) is one of most common chronic complications of diabetes mellitus (DM). The pathogenesis of DR is complex and involves interaction of many molecular mechanisms, and far not all of them have been studied.

AIM: To determine the level of matrix metalloproteinases and kynurenines in the blood of patients with type 2 DM (T2DM) with different stages of DR.

MATERIALS AND METHODS: Four groups of patients were formed: Group 1 (control) — 21 healthy individuals; Group 2 — 21 patients with prediabetes, Group 3 — 21 patients with T2DM, Group 4 — 63 patients with T2DM and DR. Then patients with DR were divided into groups (n = 21): Group 5 — non-proliferative stage of DR, Group 6 — preproliferative DR, Group 7 — proliferative DR. In the blood serum, the following parameters were determined: the content of metalloproteinases (MMP) types 2 and 9 (MMP-2, MMP-9) by the enzyme immunoassay; in blood plasma — the concentration of kynurenines by the high-performance liquid chromatography.

RESULTS: Significant differences were recorded in the studied parameters between healthy individuals and patients with diabetes. Subsequently, the results of patients with different stages of DR were compared with the data of patients with diabetes without vascular complications. In the preproliferative stage of DR, an excess of blood MMP-2 by 87.9% (p = 0.030) and MMP-9 by 37% (p = 0.049) was recorded relative to the individuals with diabetes. In the proliferative stage of DR, the levels of MMP-9 and MMP-2 were higher than those of not only the comparison group, but also the groups of non-proliferative and preproliferative stages of DR. In the preproliferative stage of DR, an increased concentration of 3-hydroxykynurenine was also recorded. The maximum increase in kynurenines was noted in the final stage of DR (p < 0.05 relative to the groups of non-proliferative and preproliferative DR).

CONCLUSIONS: In the analyzed groups of individuals, the concentrations of kynurenines increased as the underlying disease progressed. The level of MMP-9 was higher in diabetes mellitus, and in the proliferative stage of DR, the values of MMP-9 and MMP-2 increased.

Full Text

Restricted Access

About the authors

Olga A. Saklakova

Chita State Medical Academy

Email: saklakovaoa@mail.ru
ORCID iD: 0009-0007-3163-4953
SPIN-code: 6375-3450
Russian Federation, Chita

Maria V. Maksimenya

Chita State Medical Academy

Email: mmv4510@mail.ru
ORCID iD: 0000-0001-6308-3411
SPIN-code: 1875-5786

Cand. Sci. (Biology)

Russian Federation, Chita

Tatyana M. Karavaeva

Chita State Medical Academy

Author for correspondence.
Email: KaTany1@yandex.ru
ORCID iD: 0000-0002-0487-6275
SPIN-code: 5483-1547

MD, Cand. Sci. (Medicine), Associate Professor

Russian Federation, Chita

Pavel P. Tereshkov

Chita State Medical Academy

Email: tpp6915@mail.ru
ORCID iD: 0000-0002-8601-3499
SPIN-code: 5228-8808

MD, Cand. Sci. (Medicine)

Russian Federation, Chita

Anna A. Perelomova

Chita State Medical Academy

Email: savani15@mail.ru
ORCID iD: 0009-0004-5205-645X
Russian Federation, Chita

Elena V. Fefelova

Chita State Medical Academy

Email: fefelova.elena@mail.ru
ORCID iD: 0000-0002-0724-0352
SPIN-code: 4199-2842

MD, Dr. Sci. (Medicine), Associate Professor

Russian Federation, Chita

References

  1. Kowluru RA, Zhong Q, Santos JM. Matrix metalloproteinases in diabetic retinopathy: potential role of MMP-9. Expert Opin Investig Drugs. 2012;21(6):797–805. doi: 10.1517/13543784.2012.681043
  2. Filippov VM, Petrachkov DV, Budzinskaya MV, Sidamonidze AL. Modern concepts of pathogenesis of diabetic retinopathy. Vestn Oftalmol. 2021; 137(5 2):306–313. doi: 10.17116/oftalma2021137052306 EDN: MXUFMW
  3. Kang Q, Yang C. Oxidative stress and diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications. Redox Biol. 2020;37:101799. doi: 10.1016/j.redox.2020.101799 EDN: ZUSROR
  4. Wang J, Li M, Geng Z, et al. Role of Oxidative Stress in Retinal Disease and the Early Intervention Strategies: A Review. Oxid Med Cell Longev. 2022;2022:7836828. doi: 10.1155/2022/7836828 EDN: TPYIIT
  5. Mor A, Tankiewicz–Kwedlo A, Krupa A, Pawlak D. Role of Kynurenine Pathway in Oxidative Stress during Neurodegenerative Disorders. Cells. 2021;10(7):1603. doi: 10.3390/cells10071603 EDN: XLBAUY
  6. Solanki A, Bhatt LK, Johnston TP, Prabhavalkar KS. Targeting Matrix Metalloproteinases for Diabetic Retinopathy: The Way Ahead? Curr Protein Pept Sci. 2019;20(4):324–333. doi: 10.2174/1389203719666180914093109
  7. Fabrikantov OL, Lev IV, Agarkov NM, Osmanov RE. Matrix Metalloproteinases in Predicting Nonproliferative Diabetic Retinopathy in Old Age. Ophthalmology in Russia. 2022;19(4):803–807. doi: 10.18008/1816-5095-2022-4-803-807 EDN: QOSFLW
  8. Lee E-J, Zheng M, Craft CM, Jeong S. Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) are localized in the nucleus of retinal Müller glial cells and modulated by cytokines and oxidative stress. PLoS One. 2021;16(7):e0253915. doi: 10.1371/journal.pone.0253915 EDN: NTJWHK
  9. Solovev NV. Possibility of pharmacological correction of NMDA-induced retinal excitotoxicity by 3-hydroxypyridine derivatives. Sovremennyye Tekhnologii v Oftal'mologii. 2023;(2):64. (In Russ.) doi: 10.25276/2312-4911-2023-2-64-70 EDN: XYFKRQ
  10. Mudrov VA. Statistical analysis algorithms of quantitative features in biomedical research using the SPSS software package. The Transbaikalian Medical Bulletin. 2020;(1):140–150. EDN: NXHHSU
  11. Oshitari T. Neurovascular Impairment and Therapeutic Strategies in Diabetic Retinopathy. Int J Environ Res Public Health. 2021;19(1):439. doi: 10.3390/ijerph19010439 EDN: ISFFUX
  12. Roy S, Kim D. Retinal capillary basement membrane thickening: Role in the pathogenesis of diabetic retinopathy. Prog Retin Eye Res. 2021;82:100903. doi: 10.1016/j.preteyeres.2020.100903 EDN: KTAGPF
  13. Varakuta EY, Logvinov SV, Potapov AV, et al. The role of vascular changes from photoinduced retinal damage. Fundamental Research. 2014;(10, Pt 5):847–850. Available from: https://fundamental-research.ru/en/article/view?id = 35750. Accessed: 20.02.2024. EDN: SZUGNR
  14. Logatkina AV, Nikiforov VS, Bondar SS, Terkhov IV. Proinflammatory cytokines and signaling pathways in peripheral blood mononuclear cells in patients with coronary artery disease. Clinical Medicine (Russian Journal). 2017;95(3):238–244. EDN: YQAGSP
  15. Vasincu A, Rusu R-N, Ababei D-C, et al. Exploring the Therapeutic Potential of Cannabinoid Receptor Antagonists in Inflammation, Diabetes Mellitus, and Obesity. Biomedicines. 2023;11(6):1667. doi: 10.3390/biomedicines11061667 EDN: VLUVIG
  16. Frantsiyants EM, Surikova EI, Kaplieva IV, et al. Diabetes mellitus and cancer: a system of insulin-like growth factors. Problems of Endocrinology. 2021;67(5):34–42. doi: 10.14341/probl12741 EDN: KIZYWG
  17. Hematulin A, Sagan D, Eckardt–Schupp F, Moertl S. NBS1 is required for IGF-1 induced cellular proliferation through the Ras/Raf/MEK/ERK cascade. Cell Signal. 2008;20(12):2276–2285. doi: 10.1016/j.cellsig.2008.08.017
  18. Wang Q, Ding Y, Song P, et al. Tryptophan-Derived 3-Hydroxyanthranilic Acid Contributes to Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice In Vivo. Circulation. 2017;136(23):2271–2283. doi: 10.1161/circulationaha.117.030972
  19. Song P, Ramprasath T, Wang H, Zou M-H. Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases. Cell Mol Life Sci. 2017;74(16):2899–2916. doi: 10.1007/s00018-017-2504-2 EDN: KDTOHC
  20. Li Y, Kilani RT, Rahmani–Neishaboor E, et al. Kynurenine increases matrix metalloproteinase-1 and -3 expression in cultured dermal fibroblasts and improves scarring in vivo. J Invest Dermatol. 2014;134(3): 643–650. doi: 10.1038/jid.2013.303
  21. Ren R, Fang Y, Sherchan P, et al. Kynurenine/Aryl Hydrocarbon Receptor Modulates Mitochondria-Mediated Oxidative Stress and Neuronal Apoptosis in Experimental Intracerebral Hemorrhage. Antioxid Redox Signal. 2022;37(16-18):1111–1129. doi: 10.1089/ars.2021.0215 EDN: LFCBLQ
  22. Kozieł K, Urbanska EM. Kynurenine Pathway in Diabetes Mellitus-Novel Pharmacological Target? Cells. 2023;12(3):460. doi: 10.3390/cells12030460 EDN: UXUSJD
  23. Fefelova EV, Saklakova OA, Maksimenya MV, et al. Kynurenine pathway metabolites of tryptophan metabolism in the development of angiopathies during diabetes mellitus. The Transbaikalian Medical Bulletin. 2023;(2):173–189. EDN: OWWLIB

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. The content of matrix metalloproteinases in the blood of individuals with diabetes mellitus and different stages of diabetic retinopathy Me [Q1; Q3], pg/ml: ММP — matrix metalloproteinase; DR — diabetic retinopathy; DM — diabetes mellitus.

Download (43KB)
Indexing metadata
3. Fig. 2. Blood kynurenine levels in individuals with diabetes and different stages of diabetic retinopathy (Me [Q1; Q3], μmol/l): ММP — matrix metalloproteinase; DR — diabetic retinopathy; DM — diabetes mellitus.

Download (33KB)
Indexing metadata
4. Fig. 3. The role of matrix metalloproteinases and kynurenines in the development of diabetic retinopathy: In diabetes mellitus, the rate of glycation of various biopolymers increases (1), including hemoglobin. Retinal hypoxia is accompanied by overproduction of matrix metalloproteinases MMPs (2), which are involved in neovascularization (3), characteristic of proliferative DR (4). Inflammatory cytokines initiate signaling pathways (5), in particular through mitogen-activated protein kinase (MAPK) and the nuclear transcription factor NF-κB. In addition, chronic hyperinsulinemia stimulates an increase in the level of circulating IGF-1, which triggers the Ras/Raf/MAPK/ERK cascade. This mechanism leads to the activation of MMP-9 in the retina (7) and to cell death (8). MMP induction is regulated by free radical oxidation products (9) with subsequent impairment of mitochondrial function, perpetuating a vicious cycle of mitochondrial damage and MMP activation (10). Kynurenines increase the expression rate of MMPs by activating MAPK (11). Kynurenines induce changes in multiple signaling pathways through activation of the aryl hydrocarbon receptor (AhR) (12), which functions as a transcription factor and also initiates the production of reactive oxygen species (13). Some kynurenine derivatives themselves provoke oxidative stress (13). Oxidative stress accelerates cell death (14), leading to DR (15); DR — diabetic retinopathy, MMP — matrix metalloproteinase, DM — diabetes mellitus, AhR — arylcarbohydrate receptor, IGF-1 — insulin-like growth factor 1, MAPK — mitogen-activated protein kinase.

Download (79KB)
Indexing metadata

Copyright (c) 2025 Eco-Vector

License URL: https://eco-vector.com/for_authors.php#07

Media Registry Entry of the Federal Service for Supervision of Communications, Information Technology and Mass Communications (Roskomnadzor) PI No. FS77-76803 dated September 24, 2019.