Skip to main content
Log in

Influence of Tangeretin on the Exponential Regression of Inflammation and Oxidative Stress in Streptozotocin-Induced Diabetic Nephropathy

  • Original Article
  • Published:
Applied Biochemistry and Biotechnology Aims and scope Submit manuscript

Abstract

Diabetes is an amalgamation of metabolic disorders marked by hyperglycemia. Over time diabetes brings up several other complications with it like cardiovascular disease, retinopathy, neuropathy, and nephropathy. among which diabetic nephropathy (DN) is the one we are concerned about in the present study. Diabetes management requires following a healthy lifestyle with proper medication. Most of the anti-diabetic drugs available at present come with adverse side effects. Nature has provided us with several components that are anti-diabetic in nature which has fewer or no side effects and tangeretin is one among them. Tangeretin is a natural flavonoid abundantly present in orange peel and tangerines. Our study is designed to evaluate tangeretin, as an anti-diabetic medication especially for patients suffering from diabetic nephropathy. The procured healthy rats were first divided into four groups: the group I was maintained as healthy control and the others were subjected to the induction of diabetes by i.p. injection of streptozotocin (STZ) at the concentration of 55mg/kg b.wt .Then, the diabetic rats were further divided into three groups: group II was used as the diabetic control rats and the group III and group IV were administered with tangeretin (25mg/kg b.wt) and positive control drug metformin (150mg/kg b.wt) for 8 weeks. The body weight, blood glucose, and serum insulin levels were estimated at week 0 and week 8. Reactive oxygen species (ROS) inhibitory effect, antioxidant, antilipidemic, nephroprotective, and anti-inflammatory effects of tangeretin on the diabetic-induced rats were evaluated at the end of week 8 in addition to the histopathological assessment of the sections of the kidneys of the experimental rats. All the test results concluded that tangeretin was able to significantly decelerate the progression of DN in STZ-induced diabetic rats.

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

Data Availability

Not applicable.

References

  1. Sciberras, J., Camilleri, L. M., & Cuschieri, S. (2020). The burden of type 2 diabetes pre-and during the COVID-19 pandemic – A review. Journal of Diabetes & Metabolic Disorders, 19, 1357–1365.

    Article  CAS  Google Scholar 

  2. World Health Organization. Diabetes. (2018). WHO https://www.who.int/news-room/fact-sheets/detail/diabetes. Accessed 10 June 2011.

  3. International Diabetes Federation. (2021). IDF Diabetes Atlas, 10th edn. International Diabetes Federation.

  4. Tan, W. S., Arulselvan, P., Ng, S. F., Mat Taib, C. N., Sarian, M. N., & Fakurazi, S. (2019). Improvement of diabetic wound healing by topical application of Vicenin-2 hydrocolloid film on Sprague Dawley rats. BMC Complementary Medicine and Therapies, 19(1), 20.

    Article  Google Scholar 

  5. Tanios, B. Y., & Ziyadeh, F. N. (2012). Emerging therapies for diabetic nephropathy patients: beyond blockade of the renin-angiotensin system. Nephron Extra, 2, 278–282.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ganesan, P., Arulselvan, P., & Choi, D. K. (2017). Phytobioactive compound-based nanodelivery systems for the treatment of type 2 diabetes mellitus - Current status. International Journal of Nanomedicine., 12, 1097–1111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Valencia, W. M., & Florez, H. (2017). How to prevent the microvascular complications of type 2 diabetes beyond glucose control. BMJ, 356, i6505.

    Article  PubMed  Google Scholar 

  8. Thomas, M., Brownlee, M., Susztak, K., Sharma, K., Jandeleit-Dahm, K. A. M., Zoungas, S., Rossing, P., Groop, P. H., & Cooper, M. E. (2015). Diabetic kidney disease. Nature Reviews Disease Primers, 1, 15018.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Horakova, O., Kroupova, P., Bardova, K., Buresova, J., Janovska, P., Kopecky, J., & Rossmesisl, M. (2019). Metformin acutely lowers blood glucose levels by inhibition of intestinal glucose transport. Scientific Reports, 9, 6156.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Lipska, K. J., Bailey, C. J., & Inzucchi, S. E. (2011). Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care, 34, 1431–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sellamuthu, P. S., Arulselvan, P., Fakurazi, S., & Kandasamy, M. (2014). Beneficial effects of mangiferin isolated from Salacia chinensis on biochemical and hematological parameters in rats with streptozotocin induced diabetes. Pakistan Journal of Pharmaceutical Sciences, 27(1), 161–167.

    CAS  PubMed  Google Scholar 

  12. Muhammad, A. A., Arulselvan, P., Cheah, P. S., Abas, F., & Fakurazi, S. (2016). Evaluation of wound healing properties of bioactive aqueous fraction from Moringa oleifera Lam on experimentally induced diabetic animal model. Drug Design, Development and Therapy, 10, 1715–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mutha, R. E., Tatiya, A. U., & Surana, S. J. (2021). Flavonoids as natural phenolic compounds and their role in therapeutics: An overview. Future Journal of Pharmaceutical Sciences, 7, 25.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Chen, F., Ma, Y., Sun, Z., & Zhu, X. (2018). Tangeretin inhibits high glucose-induced extracellular matrix accumulation in human glomerular mesangial cells. Biomedicine & Pharmacotherapy, 102, 1077–1083.

    Article  CAS  Google Scholar 

  15. Liu, L. L., Li, F. H., Zhang, Y., Zhang, X. F., & Yang, J. (2017). Tangeretin has anti-asthmatic effects via regulating PI3K and Notch signaling and modulating Th1/Th2/Th17 cytokine balance in neonatal asthmatic mice. Brazilian Journal of Medical and Biological Research, 50(8), e5991.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Xu, S., Kong, Y. G., Jiao, W. E., Yang, R., Qiao, Y. L., Xu, Y., Tao, Z. Z., & Chen, S. M. (2019). Tangeretin promotes regulatory T cell differentiation by inhibiting notch1/jagged1 signaling in allergic rhinitis. International Immunopharmacology, 72, 402–412.

    Article  CAS  PubMed  Google Scholar 

  17. Xu, J. J., Liu, Z., Tang, W., Wang, G. C., Chung, H. Y., Liu, Q. Y., Zhuang, L., Li, M. M., & Li, Y. L. (2015). Tangeretin from citrus reticulate inhibits respiratory syncytial virus replication and associated inflammation in vivo. Journal of Agricultural and Food Chemistry, 63(43), 9520–9527.

    Article  CAS  PubMed  Google Scholar 

  18. NazariSoltan Ahmad, S., Rashtchizadeh, N., Argani, H., Roshangar, L., Ghorbanihaghjo, A., Sanajou, D., Panah, F., Jigheh, Z. A., Dastmalchi, S., & Kalantary-Charvadeh, A. (2019). Tangeretin protects renal tubular epithelial cells against experimental cisplatin toxicity. Iranian Journal of Basic Medical Sciences, 22(2), 179–186.

    Google Scholar 

  19. Omar, H. A., Mohamed, W. R., Arab, H. H., & Arafa, E. S. A. (2016). Tangeretin alleviates cisplatin-induced acute hepatic injury in rats: Targeting MAPKs and apoptosis. PLoS One, 11(3), 0151649.

    Article  CAS  Google Scholar 

  20. Cheng, Z., Surichan, S., Ruparelia, K., Arroo, R., & Boarder, M. R. (2011). Tangeretin and its metabolite 4’-hydroxytetramethoxyflavone attenuate EGF-stimulated cell cycle progression in hepatocytes; role of inhibition at the level of mTOR/p70S6K. British Journal of Pharmacology, 162, 1781–1791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Youn, K., Yu, Y., Lee, J., Jeong, W. S., Ho, C. T., & Jun, M. (2017). Polymethoxyflavones: novel β-secretase (BACE1) inhibitors from citrus peels. Nutrients, 9(9), 973.

    Article  PubMed Central  CAS  Google Scholar 

  22. Datla, K. P., Christidou, M., Widmer, W. W., Rooprai, H. K., & Dexter, D. T. (2001). Tissue distribution and neuroprotective effects of citrus flavonoid tangeretin in a rat model of Parkinson’s disease. Neuroreport, 12(17), 3871–3875.

    Article  CAS  PubMed  Google Scholar 

  23. Takano, K., Tabata, Y., Kitao, Y., Murakami, R., Suzuki, H., Yamada, M., Iinuma, M., Yoneda, Y., Ogawa, S., & Hori, O. (2007). Methoxyflavones protect cells against endoplasmic reticulum stress and neurotoxin. American Journal of Physiology-Cell Physiology, 292, C353–C361.

    Article  CAS  PubMed  Google Scholar 

  24. Zafar, M., & Naqvi, S. N. (2010). Effects of STZ-induced diabetes on the relative weights of kidney, liver and pancreas in albino rats: A comparative study. International Journal of Morphology, 28, 135–142.

    Article  Google Scholar 

  25. Sellamuthu, P. S., Arulselvan, P., Muniappan, B. P., Fakurazi, S., & Kandasamy, M. (2013). Mangiferin from Salacia chinensis prevents oxidative stress and protects pancreatic β-cells in streptozotocin-induced diabetic rats. Journal of Medicinal Food, 16(8), 719–27.

    Article  CAS  PubMed  Google Scholar 

  26. Kotb El-Sayed, M., Al-Massarani, S., El Gamel, A., El-Shaibany, A., & Al-Mahbashi, H. M. (2020). Mechanism of antidiabetic effects of Plicosepalus Acaciae flower in streptozotocin-induced type 2 diabetic rats, as complementary and alternative therapy. BMC Complement Med Ther., 20(1), 290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Xue, R., Gui, D., Zheng, L., Zhai, R., Wang, F., & Wang, N. (2017). Mechanistic insight and management of diabetic nephropathy: Recent progress and future perspective. Journal of Diabetes Research, 2017, 1839809.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Gheith, O., Farouk, N., Nampoory, N., Halim, M. A., & Al- Otaibi, T. (2015). Diabetic kidney disease: Worldwide difference of prevalence and risk factors. Journal of Nephropharmacology, 5, 49–56.

    PubMed  PubMed Central  Google Scholar 

  29. Forbes, J. M., Coughlan, M. T., & Cooper, M. E. (2008). Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes, 57, 1446–1454.

    Article  CAS  PubMed  Google Scholar 

  30. Clinical Obesity (2nd ed.). John Wiley & Sons. 2008. p. 262. ISBN 978-0-470-98708-7. Archived from the original on 8 September 2017.

  31. Ji, L., Zinman, B., Patel, S., Ji, J., Bailes, Z., Sandra Thiemann, S., & Seck, T. (2015). Efficacy and safety of linagliptin co-administered with low-dose metformin once daily versus high-dose metformin twice daily in treatment-naïve patients with type 2 diabetes: A double-blind randomized trial. Randomized Controlled Trial Advances in Therapy., 32(3), 201–215.

    CAS  PubMed  Google Scholar 

  32. Tanaka, K., Saisho, Y., Kawai, T., Tanaka, M., Meguro, S., Irie, J., Imai, T., Shigihara, T., Morimoto, J., Yajima, K., Atsumi, Y., Takei, I., & Itoh, H. (2015). Efficacy and safety of liraglutide monotherapy compared with metformin in Japanese overweight/obese patients with type 2 diabetes. Endocrine Journal, 62(5), 399–409.

    Article  CAS  PubMed  Google Scholar 

  33. Vanhoecke, W. B., Delporte, F., Van Braeckel, E., Heyerick, A., Depypere, H. T., Nuytinck, M., Keukeleire, D. D., & Bracke, M. E. (2005). A safety study of oral tangeretin and xanthohumol administration to laboratory mice. Vivo, 19(1), 103–107.

    CAS  Google Scholar 

  34. Kurowska, E. M., & Manthey, J. A. (2004). Hypolipidemic effects and absorption of citrus polymethoxylated flavones in hamsters with diet-induced hypercholesterolemia. Journal of Agricultural and Food Chemistry, 52(10), 2879–2886.

    Article  CAS  PubMed  Google Scholar 

  35. Gilman, A. G., Rall, T. W., Nies, A. S., & Tayer, P. (1990). Eds., Goodman and Gilman’s the Pharmacological Basis of Therapeutics, Pergamon Press, 8th edition.

  36. Mahimainathan, L., Das, F., Venkatesan, B., & Choudhury, G. G. (2006). Mesangial cell hypertrophy by high glucose is mediated by downregulation of the tumor suppressor PTEN. Diabetes, 55(7), 2115–2125.

    Article  CAS  PubMed  Google Scholar 

  37. Larson, M. O., Wilken, M., Gotfredsen, C. F., Carr, R. D., Svendsen, O., & Roli, B. (2002). Mild streptozotocin diabetes in the Gottingen minipig. A novel model of moderate insulin deficiency and diabetes. American Journal of Physiology-Endocrinology and Metabolism., 282, 1342–1351.

    Article  Google Scholar 

  38. Hsu, C. Y., McCulloch, C. E., Iribarren, C., Darbinian, J., & Go, A. S. (2006). Body mass index and risk for end-stage renal disease. Annals of Internal Medicine, 144(1), 21–28.

    Article  PubMed  Google Scholar 

  39. Eknoyan, G. (2007). Obesity, diabetes, and chronic kidney disease. Current Diabetes Reports, 7, 449–453.

    Article  PubMed  Google Scholar 

  40. Feng, K., Lan, Y., Zhu, X., Li, J., Chen, T., Huang, Q., Ho, C. T., Chen, Y., & Cao, Y. (2020). Hepatic lipodemics analysis reveals the anitobesity and cholesterol-lowering effects of TAN in high fat-diet fed rats. Journal of Agricultural and Food Chemistry, 68, 6142–6153.

    Article  CAS  PubMed  Google Scholar 

  41. Kim, M. S., Hur, H. J., Kwon, D. Y., & Hwang, J. T. (2012). Tangeretin stimulates glucose uptake via regulation of AMPK signaling pathways in C2C12 myotubes and improves glucose tolerance in high-fat diet-induced obese mice. Molecular and Cellular Endocrinology, 358(1), 127–134.

    Article  CAS  PubMed  Google Scholar 

  42. Sudhir, R., & Mohan, V. (2002). Postprandial hyperglycemia in patients with type 2 diabetes mellitus. Treatments in Endocrinology, 1, 105–116.

    Article  PubMed  Google Scholar 

  43. Zoungas, S., Chalmers, J., Ninomiya, T., Li, Q., Cooper, M. E., Colagiuri, S., Fulcher, G., de Galan, B. E., Harrap, S., Hamet, P., Heller, S., MacMahon, S., Marre, M., Poulter, N., Travert, F., Patel, A., Neal, B., & Woodward, M. (2012). Association of HbA1c levels with vascular complications and death in patients with type 2 diabetes: Evidence of glycaemic thresholds. Diabetologia, 55, 636–643.

    Article  CAS  PubMed  Google Scholar 

  44. Sundaram, R., Shanthi, P., & Sachdanandam, P. (2014). Effect of tangeretin, a polymethoxylated flavone on glucose metabolism in streptozotocin-induced diabetic rats. Phytomedicine, 21(6), 793–799.

    Article  CAS  PubMed  Google Scholar 

  45. Sada, K., Nishikawa, T., Kukidome, D., Yoshinaga, T., Kajihara, N., Sonoda, K., Senokuchi, T., Motoshima, H., Matsumura, T., & Araki, E. (2016). Hyperglycemia induces cellular hypoxia through production of mitochondrial ROS followed by suppression of aquaporin-1. PLoS One, 11, e0158619.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Fu, Q., Colgan, S. P., & Shelley, C. S. (2016). Hypoxia: The force that drives chronic kidney disease. Clinical Medicine & Research, 14, 15–39.

    Article  CAS  Google Scholar 

  47. Kang, M. K., Kim, S. I., Oh, S. Y., Na, W., & Kang, Y. H. (2020). Tangeretin ameliorates glucose-induced podocyte injury through blocking epithelial to mesenchymal transition caused by oxidative stress and hypoxia. International Journal of Molecular Sciences, 21(22), 8577.

    Article  CAS  PubMed Central  Google Scholar 

  48. Eurich, D. T., McAlister, F. A., Blackburn, D. F., Majumdar, S. R., Tsuyuki, R. T., Varney, J., & Johnson, J. A. (2007). Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: Systematic review. British Medical Journal, 335, 497–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kao, M. P., Ang, D. S., Pall, A., & Struthers, A. D. (2010). Oxidative stress in renal dysfunction: Mechanisms, clinical sequelae and therapeutic options. Journal of Human Hypertension, 24(1), 1–8.

    Article  CAS  PubMed  Google Scholar 

  50. Thallas-Bonke, V., Thorpe, S. R., Coughlan, M. T., Fukami, K., Yap, F. Y. T., Sourris, K. C., Penfold, S. A., Bach, L. A., Cooper, M. E., & Forbes, J. M. (2008). Inhibition of NADPH oxidase prevents advanced glycation end product-mediated damage in diabetic nephropathy through a protein kinase C-dependent pathway. Diabetes, 57(2), 460–469.

    Article  CAS  PubMed  Google Scholar 

  51. Wu, J., Zhao, Y. M., & Deng, Z. K. (2018). Tangeretin ameliorates renal failure via regulating oxidative stress, NF-κB-TNF-α/iNOS signalling and improves memory and cognitive deficits in 5/6 nephrectomized rats. Inflammopharmacology., 26(1), 119–132.

    Article  CAS  PubMed  Google Scholar 

  52. Li, W. Y., Yao, C. X., Zhang, S. F., Wang, S. L., Wang, T. Q., Xiong, C. J., Li, Y. B., & Zang, M. X. (2012). Improvement of myocardial lipid accumulation and prevention of PGC-1α induction by fenofibrate. Molecular Medicine Reports, 5, 1396–1400.

    CAS  PubMed  Google Scholar 

  53. Huang, C. C., Lo, H. C., Huang, H. H., Kao, W. F., Yen, D. H., Wang, L. M., Huang, C. I., & Lee, C. H. (2007). ED presentations of acute renal infarction. American Journal of Emergency Medicine, 25, 164–169.

    Article  PubMed  Google Scholar 

  54. Qu, X., Tang, Y., & Hua, S. (2018). Immunological approaches towards cancer and inflammation: A cross talk. Frontiers in Immunology, 9, 563.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Delaney, B., Phillips, K., Buswell, D., Mowry, B., Mickels, D., Cox, D., Wang, H. B., & Manthey, J. (2001). Immunotoxicity of a standardized citrus polymethoxylated flavone extract. Food and Chemical Toxicology, 39(11), 1087–1094.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed equally.

Corresponding author

Correspondence to Fang Liu.

Ethics declarations

Ethical Approval

Not applicable.

Consent to Participate

All authors have their consent to participate.

Consent to Publish

All authors have their consent to publish their work.

Competing Interests

The authors declare no competing interests.

Additional information

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

Sun, P., Huang, R., Qin, Z. et al. Influence of Tangeretin on the Exponential Regression of Inflammation and Oxidative Stress in Streptozotocin-Induced Diabetic Nephropathy. Appl Biochem Biotechnol 194, 3914–3929 (2022). https://doi.org/10.1007/s12010-022-03920-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12010-022-03920-w

Keywords

Navigation