Morin hidrat, böbrek dokularında oksidatif stresi ve 8-hidroksideoksiguanozin'i inhibe ederek diyabetik nefropati’yi önler

Abstract

Amaçlar: Bu çalışmanın amacı, diyabetik nefropatili sıçanların böbrek dokusunda oksidatif stres ve 8-hidroksideoksiguanozin'i (8-OHdG) hedef alarak, morin hidratın tek başına veya metformin ile birlikte kullanımının diyabetik nefropatiye karşı koruyucu etkisini araştırmaktır. Metotlar: Bu deneysel çalışmada, sıçanlara streptozotosin (STZ) enjeksiyonu ile diyabetik nefropati oluşturuldu. Morin hidratın diyabetik nefropatiyi inhibe etme yeteneği, biyokimyasal, immünohistokimyasal ve immünofloresan yöntemleri kullanılarak böbrek dokularında oksidatif stres parametreleri olan lipid peroksidasyonu (LPO), glutatyon, glutatyon peroksidaz, süperoksit dismutaz ve katalaz; DNA hasar belirteci olan 8-OHdG; böbrek hasarı belirteci olan kidney injury molekül-1 (KIM-1) ve aquaporin; ve serum örneklerinde böbrek fonksiyonunun belirteçleri olan kreatinin ve kan üre azotunu ölçümü ile test edildi. Bulgular: STZ uygulamasından sonra LPO, 8-OHdG, KIM-1 ve aquaporin düzeylerinde anlamlı artışlar (p < 0.0001) ve glutatyon, glutatyon peroksidaz, süperoksit dismutaz ve katalaz düzeylerinde anlamlı düşüşler (p < 0.0001) gözlemlenmiştir. Bu da diyabetik nefropatinin geliştiğini ve ilerlediğini göstermektedir. Morin hidrat ile tedavi, özellikle metformin ile birlikte uygulandığında oksidan düzeylerini baskıladığı, antioksidan sistemi ve böbreğin histolojik yapı bütünlüğünü iyileştirdiği gözlenmiştir. Bu durumun KIM-1 ve aquaporin düzeylerine ve böbrek fonksiyon belirteçlerine olumlu olarak yansıdığı görülmüştür. Sonuç: Morin hidrat, böbrek dokularında oksidatif stresi ve 8-OHdG düzeylerini baskılayarak diyabetes mellitus kaynaklı diyabetik nefropatiyi önler. Bu nedenle, bu biyoflavonoid, diyabetik nefropatisi olan hastalar için umut verici bir adaydır. Ayrıca, morin hidrat-metformin kombinasyon tedavisi, tek başına uygulanan tedaviye göre daha iyi bir etkinlik sağlamış olup, bu da morin hidrat ve metforminin diyabetik nefropatili hastaların tedavisinde önemli bir sinerjik rol oynayacağını ifade etmektedir.

Keywords

• Morin Hidrat
• Oksidatif Stres
• 8-OHdG
• Diyabetik Nefropati
• KIM-1

Morin hydrate prevents diabetic nephropathy by suppressing oxidative stress and 8-hydroxydeoxyguanosine in kidney tissues

Abstract

Aims: The aim of this study was to investigate the protective effect of morin hydrate either individually or in combination with metformin against diabetic nephropathy by targeting oxidative stress and 8-hydroxydeoxyguanosine (8-OHdG) in the kidney tissue of rats with diabetic nephropathy. Methods: In this experimental study, diabetic nephropathy was induced in rats by injection of streptozotocin (STZ). The ability of morin hydrate to inhibit diabetic nephropathy was tested by screening lipid peroxidation (LPO), glutathione, glutathione peroxidase, superoxide dismutase, and catalase as parameters of oxidative stress; 8-OHdG as a marker of DNA damage and kidney injury molecule-1 (KIM-1) and aquaporin as indicators of kidney injury in renal tissues; and serum creatinine and blood urea nitrogen as markers of renal function using biochemical, immunohistochemical, and immunofluorescence methods. Results: Significant increases (p<0.0001) in LPO, 8-OHdG, KIM-1, and aquaporin levels and significant decreases (p<0.0001) in glutathione, glutathione peroxidase, superoxide dismutase, and catalase levels were observed after STZ administration, indicating the development and progression of diabetic nephropathy. Treatment with morin hydrate, especially in combination with metformin, suppressed the oxidant levels and improved the antioxidant system and the histopathological integrity of the kidney, which was positively reflected in the levels of KIM-1, aquaporin, and kidney function parameters. Conclusion: Morin hydrate prevents diabetic nephropathy resulting from diabetes mellitus by suppressing oxidative stress and 8-OHdG levels in kidney tissues. Therefore, this bioflavonoid represents a promising candidate for patients with diabetic nephropathy. Moreover, the combination therapy of morin hydrate and metformin achieved better effectiveness than the single treatment, which emphasizes an important synergistic role of morin hydrate and metformin in managing patients with diabetic nephropathy.

Keywords

• Morin hydrate
• oxidative stress
• 8-OHdG
• diabetic nephropathy
• KIM-1

References

1. Młynarska E, Buławska D, Czarnik W, et al. Novel insights into diabetic kidney disease. Int J Mol Sci. 2024;25(18):10222. doi:10.3390/ijms251810222
2. Sifuentes-Franco S, Padilla-Tejeda DE, Carrillo-Ibarra S, Miranda-Díaz AG. Oxidative stress, apoptosis, and mitochondrial function in diabetic nephropathy. Int J Endocrinol. 2018;2018:1875870. doi:10.1155/2018/ 1875870
3. Abegaz TM, Diaby V, Sherbeny F, Ali AA. Cost effectiveness of dapagliflozin added to standard of care for the management of diabetic nephropathy in the USA. Clin Drug Investig. 2022;42:501-511. doi:10. 1007/s40261-022-01160-8
4. Wang Q, Cheng H, Jiang S, et al. The relationship between diabetic retinopathy and diabetic nephropathy in type 2 diabetes. Front Endocrinol. 2024;15:1292412. doi:10.3389/fendo.2024.1292412
5. Jia Y, Gu Y, Wang L, Jiang N, Yu X, Tian H. Critical analysis of hot topics in diabetic nephropathy related experimental research: a bibliometric analysis from 2018 to 2024. J Tissue Viability. 2025;34:100854. doi:10. 1016/j.jtv.2025.100854
6. Pelle MC, Provenzano M, Busutti M, et al. Up-Date on diabetic nephropathy. Life. 2022;12(8):1202. doi:10.3390/life12081202
7. Lin W, Chen C, Guan H, Du X, Li J. Hospitalization of elderly diabetic patients: characteristics, reasons for admission, and gender differences. BMC Geriatr. 2016;16:160. doi:10.1186/s12877-016-0333-z
8. Chen X, Xie N, Feng L, et al. Oxidative stress in diabetes mellitus and its complications: from pathophysiology to therapeutic strategies. Chin Med J. 2025;138(1):15-27. doi:10.1097/CM9.0000000000003230

9. Spoto B, Politi C, Pizzini P, et al. 8-hydroxy-2′-deoxyguanosine, a biomarker of oxidative DNA injury, in diabetic kidney disease. Nutr Metab Cardiovasc Dis. 2025;35:103722. doi:10.1016/j.numecd.2024.08.015
10. Rajput SA, Wang X, Yan HC. Morin hydrate: a comprehensive review on novel natural dietary bioactive compound with versatile biological and pharmacological potential. Biomed Pharmacother. 2021;138:111511. doi: 10.1016/j.biopha.2021.111511
11. Folorunso IM, Lawal AO, Elekofehinti OO, Iwaloye O. Hepatoprotective effect of morin hydrate in type 2 diabetic wistar rats exposed to diesel exhaust particles. Appl Biochem Biotechnol. 2023;195:5855-5880. doi:10. 1007/s12010-023-04366-4
12. Lawal AO, Folorunso IM, Iwaloye O. Morin hydrate protects type-2-diabetic wistar rats exposed to diesel exhaust particles from inflammation and oxidative stress. J Diabetes Metab Disord. 2022;21: 805-816. doi:10.1007/s40200-022-01057-5
13. Ola MS, Aleisa AM, Al-Rejaie SS, et al. Flavonoid, morin inhibits oxidative stress, inflammation and enhances neurotrophic support in the brain of streptozotocin-induced diabetic rats. Neurol Sci. 2014;35: 1003-1008. doi:10.1007/s10072-014-1628-5
14. Lawal AO, Folorunso IM, Adebisi O, Koledoye OF, Iwaloye O. Morin hydrate promotes nephrin expression through modulation of Notch1-Snail signalling pathway in diabetic rats. Asp Mol Med. 2023;2:100019. doi:10.1016/j.amolm.2023.100019
15. Hafez SM, Ibrahim HF, Abdelmohsen SR, Yasin NAE, Abouelela YS, Aboelsoud HA. The potential protective effect of propolis on diabetic nephropathy induced by streptozotocin in adult albino rats. Ultrastruct Pathol. 2024;48(5):338-350. doi:10.1080/01913123.2024.2386009
16. Belhan S, Yıldırım S, Huyut Z, Özdek U, Oto G, Algül S. Effects of curcumin on sperm quality, lipid profile, antioxidant activity and histopathological changes in streptozotocin-induced diabetes in rats. Andrologia. 2020;00:e13584. doi:10.1111/and.13584
17. Kuzu M, Kandemir FM, Yildirim S, Kucukler S, Caglayan C, Turk E. Morin attenuates doxorubicin-induced heart and brain damage by reducing oxidative stress, inflammation and apoptosis. Biomed Pharmacother. 2018;106:443-453. doi:10.1016/j.biopha.2018.06.161
18. Alhilal M, Erol HS, Yildirim S, et al. Medicinal evaluation and molecular docking study of osajin as an anti-inflammatory, antioxidant, and antiapoptotic agent against sepsis-associated acute kidney injury in rats. Ren Fail. 2024;46(2):2379008. doi:10.1080/0886022X.2024.2379008
19. Duni A, Liakopoulos V, Roumeliotis S, Peschos D, Dounousi E. Oxidative stress in the pathogenesis and evolution of chronic kidney disease: Untangling ariadne’s thread. Int J Mol Sci. 2019;20(15):3711. doi:10.3390/ijms20153711
20. Hojs NV, Bevc S, Ekart R, Hojs R. Oxidative stress markers in chronic kidney disease with emphasis on diabetic nephropathy. Antioxidants. 2020;9(10):925. doi:10.3390/antiox9100925
21. Goycheva P, Petkova-Parlapanska K, Georgieva E, Karamalakova Y, Nikolova G. Biomarkers of oxidative stress in diabetes mellitus with diabetic nephropathy complications. Int J Mol Sci. 2023;24(17):13541. doi:10.3390/ijms241713541
22. Farkas O, Jakus J, Héberger K. Quantitative structure-antioxidant activity relationships of flavonoid compounds. Molecules. 2004;9(12): 1079-1088. doi:10.3390/91201079
23. Bahramzadeh A, Tehrani SS, Goodarzi G, Seyyedebrahimi SS, Meshkani R. Combination therapy of metformin and morin attenuates insulin resistance, inflammation, and oxidative stress in skeletal muscle of high-fat diet-fed mice. Phyther Res. 2024;38(2):912-924. doi:10.1002/ptr.8086
24. Zhang Z, Huang Q, Zhao D, Lian F, Li X, Qi W. The impact of oxidative stress-induced mitochondrial dysfunction on diabetic microvascular complications. Front Endocrinol (Lausanne). 2023;14:1112363. doi:10. 3389/fendo.2023.1112363
25. Urbaniak SK, Boguszewska K, Szewczuk M, Kázmierczak-Barańska J, Karwowski BT. 8-Oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) as a potential biomarker for gestational diabetes mellitus (GDM) development. Molecules. 2020; 25(1):202. doi:10.3390/molecules25010202
26. Avci E, Çakir E, Cevher SC, Yaman H, Agilli M, Bilgi C. Determination of oxidative stress and cellular inflammation in patients with diabetic nephropathy and non-diabetic nephropathy being administered hemodialysis treatment due to chronic renal failure. Ren Fail. 2014;36(5): 767-773. doi:10.3109/0886022X.2014.890841
27. Xu GW, Yao QH, Weng QF, Su BL, Zhang X, Xiong JH. Study of urinary 8-hydroxydeoxyguanosine as a biomarker of oxidative DNA damage in diabetic nephropathy patients. J Pharm Biomed Anal. 2004;36(1):101-104. doi:10.1016/j.jpba.2004.04.016
28. Alhilal M, Yıldırım S, Erol HS, et al. Osajin is a promising candidate for sepsis-induced brain damage via suppression of the 8-OHdG/Bax/caspase-3 pathway in a rat model of sepsis. J Health Sci Med. 2025;8(2): 191-196. doi:10.32322/jhsm.1614590
29. Gena P, Pellegrini-Calace M, Biasco A, Svelto M, Calamita G. Aquaporin membrane channels: biophysics, classification, functions, and possible biotechnological applications. Food Biophys. 2011;6(2):241-249. doi:10.1007/s11483-010-9193-9
30. Rossi L, Nicoletti MC, Carmosino M, et al. Urinary excretion of kidney aquaporins as possible diagnostic biomarker of diabetic nephropathy. J Diabetes Res. 2017;2017:4360357. doi:10.1155/2017/4360357
31. Tamma G, Valenti G, Grossini E, et al. Aquaporin membrane channels in oxidative stress, cell signaling, and aging: recent advances and research trends. Oxid Med Cell Longev. 2018;2018:1501847. doi:10.1155/ 2018/1501847
32. Yu J, Da J, Yu F, Yuan J, Zha Y. HMGN1 down-regulation in the diabetic kidney attenuates tubular cells injury and protects against renal inflammation via suppressing MCP-1 and KIM-1 expression through TLR4. J Endocrinol Invest. 2024;47:1015-1027. doi:10.1007/s40618-023-02292-0
33. Hwang S, Park J, Kim J, et al. Tissue expression of tubular injury markers is associated with renal function decline in diabetic nephropathy. J Diabetes Complications. 2017;31(12):1704-1709. doi:10.1016/j.jdiacomp. 2017.08.009
34. Ahmed SA, Hamed MA. Kidney injury molecule-1 as a predicting factor for inflamed kidney, diabetic and diabetic nephropathy Egyptian patients. J Diabetes Metab Disord. 2015;14(6):6. doi:10.1186/s40200-015-0131-8
35. Çomaklı S, Kandemir FM, Küçükler S, Özdemir S. Morin mitigates ifosfamide induced nephrotoxicity by regulation of NF-kappaB/p53 and Bcl-2 expression. Biotech Histochem. 2022;97(6):423-432. doi:10.1080/10520295. 2021.2021449
36. Ávila M, Mora Sánchez MG, Bernal Amador AS, Paniagua R. The metabolism of creatinine and its usefulness to evaluate kidney function and body composition in clinical practice. Biomolecules. 2025;15(1):41. doi:10.3390/biom15010041
37. Bayrakçı S, Eygi E. Prognostic value of blood urea nitrogen to albumin ratio in elderly critically Ill patients with acute kidney injury: a retrospective study. Med. 2025;61(7):1233. doi:10.3390/medicina 61071233