Protective effects of Strychnos potatorum seed extract on diabetic nephropathy in rats: Downregulation of FSP-1 expression

Abarajitha Shankaranarayanan; Manickam Subramanian; Jones Eben Raj Thomson; Senthil Kumar Anbumani

doi:10.7324/JAPS.2025.233971

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Abstract

Diabetic nephropathy (DN), a complication of diabetes mellitus, is the primary cause of chronic kidney disease. Fibroblast-specific protein-1 (FSP-1) is a key protein involved in renal fibrosis through the epithelial-mesenchymal transition. Strychnos potatorum, a plant with various health benefits, has been studied for its potential to modulate FSP-1 expression in diabetic nephropathic rats. Thirty adult male Wistar albino rats were divided into five groups and treated with an ethanolic extract of S. potatorum seeds (500 mg/kg) and metformin (50 mg/kg) for 30 days. Biochemical parameters, renal histopathology, and FSP-1immuno-histochemistry, gene, and protein expressions were analyzed. The S. potatorum-treated group showed serum creatinine, urea, blood urea nitrogen, and glucose values of 0.70 ± 0.06, 39 ± 1.41, 19.31 ± 0.38, and 144.67 ± 8.71 mg/dl, respectively, which were significantly lower than those in the untreated diabetic group. Excessive collagen deposition, atrophied renal tubules, and perivascular fibrosis observed in diabetic animals were attenuated in the S. potatorum-treated group. The gene and protein expression of FSP-1 was significantly reduced in the S. potatorum-treated group than in the untreated diabetic animals. Strychnos potatorum by attenuating the expression of FSP-1 has arrested the epithelial-mesenchymal transition and restored the normalcy of the podocyte’s slit diaphragm. Strychnos potatorum’s modulatory effect on FSP-1 could be attributed to its antioxidant and anti-inflammatory activities. Strychnos potatorum seeds could be a promising drug for the treatment of DN pending clinical trials.

Keyword: Diabetic nephropathy Strychnos potatorum metformin FSP-1 epithelialmesenchymal transition

Citation:

Shankaranarayanan A, Subramanian M, Thomson JER, Anbumani SK. Protective effects of Strychnos potatorum seed extract on diabetic nephropathy in rats: Downregulation of FSP-1 expression. J Appl Pharm Sci. 2025;15(07):193–202. http://doi.org/10.7324/JAPS.2025.233971

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Reference

1. Mestry SN, Dhodi JB, Kumbhar SB, Juvekar AR. Attenuation of diabetic nephropathy in streptozotocin-induced diabetic rats by Punica granatum Linn. leaves extract. J Tradit Complement Med. 2017;7(3):273-80. https://doi.org/10.1016/j.jtcme.2016.06.008
2. Dhasarathan P, Theriappan P. Evaluation of antidiabetic activity of Strychonous potatorum in alloxan induced diabetic rats. J Med Med Sci. 2011;2(2):670-4.
3. Giralt-López A, Molina-Van den Bosch M, Vergara A, García-Carro C, Seron D, Jacobs-Cachá C, et al. Revisiting experimental models of diabetic nephropathy. Int J Mol Sci. 2020;21(10):3587. https://doi.org/10.3390/ijms21103587
4. Kikuchi Y, Yamada M, Imakiire T, Kushiyama T, Higashi K, Hyodo N, et al. A Rho-kinase inhibitor, fasudil, prevents development of diabetes and nephropathy in insulin-resistant diabetic rats. J Endocrinol. 2007;192(3):595-603. https://doi.org/10.1677/JOE-06-0045
5. Kang MK, Park SH, Choi YJ, Shin D, Kang YH. Chrysin inhibits diabetic renal tubulointerstitial fibrosis through blocking epithelial to mesenchymal transition. J Mol Med. 2015;93:759-72. https://doi.org/10.1007/s00109-015-1301-3
6. Strutz F, Zeisberg M, Ziyadeh FN, Yang CQ, Kalluri R, Müller GA, Neilson EG, et al. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int. 2002;61(5):1714-28. https://doi.org/10.1046/j.1523-1755.2002.00333.x
7. Strutz F, Okada H, Lo CW, Danoff T, Carone RL, Tomaszewski JE, et al. Identification and characterization of a fibroblast marker: FSP1. J Cell Biol. 1995;130(2):393-405. https://doi.org/10.1083/jcb.130.2.393
8. Kuncio GS, Neilson EG, Haverty T. Mechanisms of tubulointerstitial fibrosis. Kidney Int. 1991;39(3):550-6. https://doi.org/10.1038/ki.1991.63
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10. Wang GG, Lu XH, Li W, Zhao X, Zhang C. Protective effects of luteolin on diabetic nephropathy in STZ-induced diabetic rats. Evid Based Complementary Altern Med. 2011;2011(1):323171. https://doi.org/10.1155/2011/323171
11. Alarcon-Aguilara FJ, Roman-Ramos R, Perez-Gutierrez S, Aguilar- Contreras A, Contreras-Weber CC, Flores-Saenz JL. Study of the anti-hyperglycemic effect of plants used as antidiabetics. J Ethnopharmacol. 1998;61(2):101-10. https://doi.org/10.1016/S0378-8741(98)00020-8
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28. Gross ML, Ritz E, Schoof A, Adamczak M, Koch A, Tulp O, et al. Comparison of renal morphology in the Streptozotocin and the SHR/ N-cp models of diabetes. Lab Invest. 2004;84(4):452-64. https://doi.org/10.1038/labinvest.3700052
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30. Sanmugapriya E, Venkataraman S. Studies on hepatoprotective and antioxidant actions of Strychnos potatorum Linn. seeds on CCl4- induced acute hepatic injury in experimental rats. J Ethnopharmacol. 2006;105(1-2):154-60. https://doi.org/10.1016/j.jep.2005.10.028
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1. Mestry SN, Dhodi JB, Kumbhar SB, Juvekar AR. Attenuation of diabetic nephropathy in streptozotocin-induced diabetic rats by Punica granatum Linn. leaves extract. J Tradit Complement Med. 2017;7(3):273-80. https://doi.org/10.1016/j.jtcme.2016.06.008

2. Dhasarathan P, Theriappan P. Evaluation of antidiabetic activity of Strychonous potatorum in alloxan induced diabetic rats. J Med Med Sci. 2011;2(2):670-4.

3. Giralt-López A, Molina-Van den Bosch M, Vergara A, García-Carro C, Seron D, Jacobs-Cachá C, et al. Revisiting experimental models of diabetic nephropathy. Int J Mol Sci. 2020;21(10):3587. https://doi.org/10.3390/ijms21103587

4. Kikuchi Y, Yamada M, Imakiire T, Kushiyama T, Higashi K, Hyodo N, et al. A Rho-kinase inhibitor, fasudil, prevents development of diabetes and nephropathy in insulin-resistant diabetic rats. J Endocrinol. 2007;192(3):595-603. https://doi.org/10.1677/JOE-06-0045

5. Kang MK, Park SH, Choi YJ, Shin D, Kang YH. Chrysin inhibits diabetic renal tubulointerstitial fibrosis through blocking epithelial to mesenchymal transition. J Mol Med. 2015;93:759-72. https://doi.org/10.1007/s00109-015-1301-3

6. Strutz F, Zeisberg M, Ziyadeh FN, Yang CQ, Kalluri R, Müller GA, Neilson EG, et al. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int. 2002;61(5):1714-28. https://doi.org/10.1046/j.1523-1755.2002.00333.x

7. Strutz F, Okada H, Lo CW, Danoff T, Carone RL, Tomaszewski JE, et al. Identification and characterization of a fibroblast marker: FSP1. J Cell Biol. 1995;130(2):393-405. https://doi.org/10.1083/jcb.130.2.393

8. Kuncio GS, Neilson EG, Haverty T. Mechanisms of tubulointerstitial fibrosis. Kidney Int. 1991;39(3):550-6. https://doi.org/10.1038/ki.1991.63

9. Le Hir M, Hegyi I, Cueni-Loffing D, Loffing J, Kaissling B. Characterization of renal interstitial fibroblast-specific protein 1/ S100A4-positive cells in healthy and inflamed rodent kidneys. Histochem Cell Biol. 2005;123:335-46. https://doi.org/10.1007/s00418-005-0788-z

10. Wang GG, Lu XH, Li W, Zhao X, Zhang C. Protective effects of luteolin on diabetic nephropathy in STZ-induced diabetic rats. Evid Based Complementary Altern Med. 2011;2011(1):323171. https://doi.org/10.1155/2011/323171

11. Alarcon-Aguilara FJ, Roman-Ramos R, Perez-Gutierrez S, Aguilar- Contreras A, Contreras-Weber CC, Flores-Saenz JL. Study of the anti-hyperglycemic effect of plants used as antidiabetics. J Ethnopharmacol. 1998;61(2):101-10. https://doi.org/10.1016/S0378-8741(98)00020-8

12. Arunthathi K. Exploring anti-diabetic compounds from the ethanolic extraction of Strychnos potatorum seeds: ligand- based design, molecular dynamics. YMER. 2023;22(01):435-44.

13. Yadav KN, Kadam PV, Patel JA, Patil MJ. Strychnos potatorum: phytochemical and pharmacological review. Phcog Rev. 2014;8(15):61. https://doi.org/10.4103/0973-7847.125533

14. Sanmugapriya E, Venkataraman S. Toxicological investigations on Strychnos potatorum Linn seeds in experimental animal models. Phcog Rev. 2006;52(4):339-43. https://doi.org/10.1248/jhs.52.339

15. Varghese R, Moideen MM, Suhail MJM, Dhanapal CK. Nephroprotective effect of ethanolic extract of Strychnos potatorum seeds in rat models. Res J Pharm Biol Chem Sci. 2011;2(3):521-9.

16. Wang L, Weller CL. Recent advances in extraction of nutraceuticals from plants. Trends Food Sci Technol. 2006;17(6):300-12. https://doi.org/10.1016/j.tifs.2005.12.004

17. Punithavathi VR, Prince PS, Kumar R, Selvakumari J. Antihyperglycaemic, antilipid peroxidative and antioxidant effects of gallic acid on streptozotocin induced diabetic Wistar rats. Eur J Pharmacol. 2011;650(1):465-71. https://doi.org/10.1016/j.ejphar.2010.08.059

18. Government of India. Compendium of CPCSEA 2018 [Internet]. New Delhi: Government of India; 2018 [cited 2025 Feb 11]. Available from: https://ccsea.gov.in/WriteReadData/userfiles/file/ Compendium%20of%20CPCSEA.pdf

19. Langenfeld NJ, Payne LE, Bugbee B. Colorimetric determination of urea using diacetyl monoxime with strong acids. PLoS One. 2021;16(11):e0259760. https://doi.org/10.1371/journal.pone.0259760

20. Mishra SB, Verma A, Vijayakumar M. Preclinical valuation of anti-hyperglycemic and antioxidant action of Nirmali (Strychnos potatorum) seeds in streptozotocin-nicotinamide-induced diabetic Wistar rats: a histopathological investigation. Biomark Genomic Med. 2013;5(4):157-63. https://doi.org/10.1016/j.bgm.2013.07.010

21. Tsai GY, Cui JZ, Syed H, Xia Z, Ozerdem U, McNeill JH, et al. Effect of Nacetylcysteine on the early expression of inflammatory markers in the retina and plasma of diabetic rats. Clin Exp Ophthalmol. 2009;37(2):223-31. https://doi.org/10.1111/j.1442-9071.2009.02000.x

22. Sharun K, Banu SA, Mamachan M, Subash A, Mathesh K, Kumar R, et al. Comparative evaluation of masson's trichrome and picrosirius red staining for digital collagen quantification using ImageJ in rabbit wound healing research. JEBAS. 2023;11(5):822-33. https://doi.org/10.18006/2023.11(5).822.833

23. Crowe AR, Yue W. Semi-quantitative determination of protein expression using immunohistochemistry staining and analysis: an integrated protocol. Bio Protoc. 2019;9(24):e3465. https://doi.org/10.21769/BioProtoc.3465

24. Noshahr ZS, Salmani H, Khajavi Rad A, Sahebkar A. Animal models of diabetes-associated renal injury. J Diabetes Res. 2020;2020:9416419. https://doi.org/10.1155/2020/9416419

25. Badole SL, Jangam GB. Animal models of diabetic cardiomyopathy. In: Watson RR, Dokken BB, editors. Glucose intake and utilization in pre-diabetes and diabetes. Amsterdam, Netherlands: Academic Press; 2015. pp. 181-90. https://doi.org/10.1016/B978-0-12-800093-9.00014-4

26. Carpenter L, Cordery D, Biden TJ. Inhibition of protein kinase C δ protects rat INS-1 cells against interleukin-1β and streptozotocin-induced apoptosis. Diabetes. 2002;51(2):317-24. https://doi.org/10.2337/diabetes.51.2.317

27. Bendayan M. Immunocytochemical detection of advanced glycated end products in rat renal tissue as a function of age and diabetes. Kidney Int. 1998;54(2):438-47. https://doi.org/10.1046/j.1523-1755.1998.00030.x

28. Gross ML, Ritz E, Schoof A, Adamczak M, Koch A, Tulp O, et al. Comparison of renal morphology in the Streptozotocin and the SHR/ N-cp models of diabetes. Lab Invest. 2004;84(4):452-64. https://doi.org/10.1038/labinvest.3700052

29. Brenna Ø, Qvigstad G, Brenna E, Waldum HL. Cytotoxicity of streptozotocin on neuroendocrine cells of the pancreas and the gut. Dig Dis Sci. 2003;48:906-10. https://doi.org/10.1023/A:1023043411483

30. Sanmugapriya E, Venkataraman S. Studies on hepatoprotective and antioxidant actions of Strychnos potatorum Linn. seeds on CCl4- induced acute hepatic injury in experimental rats. J Ethnopharmacol. 2006;105(1-2):154-60. https://doi.org/10.1016/j.jep.2005.10.028

31. Singh AK, Dhar DN. Studies on the chemical constituents of the seeds of Strychnos potatorum L. Part I. Planta Med. 1977;32(08):362-7. https://doi.org/10.1055/s-0028-1097613

32. Al-Tameme HJ, Hadi MY, Hameed IH. Phytochemical analysis of Urtica dioica leaves by fourier-transform infrared spectroscopy and gas chromatography-mass spectrometry. J Pharmacognosy Phytother. 2015;7(10):238-52. https://doi.org/10.5897/JPP2015.0361

33. Tan H, Chen J, Li Y, Li Y, Zhong Y, Li G, et al. Glabridin, a bioactive component of licorice, ameliorates diabetic nephropathy by regulating ferroptosis and the VEGF/Akt/ERK pathways. Mol Med. 2022;28(1):58. https://doi.org/10.1186/s10020-022-00481-w

34. Dey P, Kundu A, Lee HE, Kar B, Vishal V, Dash S, et al. Molineria recurvata ameliorates streptozotocin-induced diabetic nephropathy through antioxidant and anti-inflammatory pathways. Molecules. 2022;27(15):4985. https://doi.org/10.3390/molecules27154985

35. Lin HH, Tseng CY, Yu PR, Ho HY, Hsu CC, Chen JH. Therapeutic effect of Desmodium caudatum extracts on alleviating diabetic nephropathy mice. Plant Foods Hum Nutr. 2024;79(2):374-80. https://doi.org/10.1007/s11130-024-01192-9

36. Mason RM, Wahab NA. Extracellular matrix metabolism in diabetic nephropathy. JASN. 2003;14(5):1358-73. https://doi.org/10.1097/01.ASN.0000065640.77499.D7

37. Badid C, Desmouliere A, Babici D, Hadj-Aissa A, McGregor B, Lefrancois N, et al. Interstitial expression of α-SMA: an early marker of chronic renal allograft dysfunction. Nephrol Dial Transplant. 2002;17(11):1993-8. https://doi.org/10.1093/ndt/17.11.1993

38. Ziyadeh FN. Mediators of diabetic renal disease: the case for TGF-β as the major mediator. JASN. 2004;15(1_suppl):S55-7. https://doi.org/10.1097/01.ASN.0000093460.24823.5B

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