Troxerutin alleviates kidney injury in rats via PI3K/AKT pathway by enhancing MAP4 expression

  • Tongxu Guan Northeast Agricultural University
  • Yingce Zheng Northeast Agricultural University
  • Shengzi Jin Northeast Agricultural University
  • Shuang Wang Northeast Agricultural University
  • Mengxin Hu
  • Xingyao Liu Northeast Agricultural University
  • Siqi Huang Northeast Agricultural University
  • Yun Liu Northeast Agricultural University
Keywords: troxerutin, kidney injury, cellular apoptosis, MAP4, PI3K/AKT pathway

Abstract

Background: Troxerutin is a flavonoid compound and possesses potential anti-cancer, antioxidant, and anti-inflammatory activities. Besides, cisplatin is one of the most widely used therapeutic agents, but the clinical uses of cisplatin are often associated with multiple side effects, among which nephrotoxicity is more common.

Objective and design: This study explored the protective effects of troxerutin (150 mg kg−1 day−1 for 14 days) against cisplatin-induced kidney injury and the potential mechanism using Wistar rats as an experimental mammalian model.

Results: We discovered that troxerutin could significantly alleviate cisplatin-induced renal dysfunction, such as increased levels of blood urea nitrogen and creatinine (P < 0.01), as well as improved abnormal renal tissue microstructure and ultrastructure. Additionally, troxerutin significantly decreased malondialdehyde (MDA), hydrogen peroxide (H2O2), NO, inducible nitric oxide synthase (iNOS) levels (P < 0.01), p-NF-κB p65/NF-κB p65, TNF-α, Pro-IL-1β, IL-6, B cell lymphoma-2 (Bcl-2)/Bcl-xl associated death promoter (Bad), Cytochrome C (Cyt C), Cleaved-caspase 9, Cleaved-caspase 3, and Cleaved-caspase 8 protein levels (P < 0.01) in the kidney tissues of cisplatin-treated rats; and increased superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), total antioxidant capacity (T-AOC) activities (P < 0.01), IL-10, Bcl-2 protein levels (P < 0.01).

Conclusion: These results suggested that the underlying mechanism might be attributed to the regulation of Phosphoinositide 3 kinase/Protein kinase B (PI3K/AKT) pathway via enhancing MAP4 expression to attenuate cellular apoptosis, alleviating oxidative stress and inflammatory response.

Downloads

Download data is not yet available.

References


  1. Kang HR, Lee D, Eom HJ, Lee SR, Lee KR, Kang KS, et al. Identification and mechanism of action of renoprotective constituents from peat moss Sphagnum palustre in cisplatin-induced nephrotoxicity. J Funct Foods 2016; 20: 358–68. doi: 10.1016/j.jff.2015.11.010

  2. Garutti M, Pelizzari G, Bartoletti M, Malfatti MC, Gerratana L, Tell G, et al. Platinum salts in patients with breast cancer: a focus on predictive factors. Int J Mol Sci 2019; 20: 3390. doi: 10.3390/ijms20143390

  3. Ghosh S. Cisplatin: the first metal based anticancer drug. Bioorg Chem 2019; 88: 102925. doi: 10.1016/j.bioorg.2019.102925

  4. Qiao G, Xu H, Li C, Li X, Farooqi AA, Zhao Y, et al. Granulin a synergizes with cisplatin to inhibit the growth of human hepatocellular carcinoma. Int J Mol Sci 2018; 19: 3060. doi: 10.3390/ijms19103060

  5. Kuhlmann MK, Burkhardt G, Köhler H. Insights into potential cellular mechanisms of cisplatin nephrotoxicity and their clinical application. Nephrol Dial Transplant 1997; 12: 2478–80. doi: 10.1093/ndt/12.12.2478

  6. dos Santos NAG, Rodrigues MAC, Martins NM, dos Santos AC. Cisplatin-induced nephrotoxicity and targets of nephroprotection: an update. Arch Toxicol 2012; 86: 1233–50. doi: 10.1007/s00204-012-0820-7

  7. Crona DJ, Faso A, Nishijima TF, McGraw KA, Galsky MD, Milowsky MI. A systematic review of strategies to prevent cisplatin-induced nephrotoxicity. Oncologist 2017; 22: 609–19. doi: 10.1634/theoncologist.2016-0319

  8. Salama SA, Arab HH, Maghrabi IA. Troxerutin down-regulates KIM-1, modulates p38 MAPK signaling, and enhances renal regenerative capacity in a rat model of gentamycin-induced acute kidney injury. Food Funct 2018; 9: 6632–42. doi: 10.1039/c8fo01086b

  9. Yang X, Xu W, Huang K, Zhang B, Wang H, Zhang X, et al. Precision toxicology shows that troxerutin alleviates ochratoxin A-induced renal lipotoxicity. FASEB J 2019; 33: 2212–27. doi: 10.1096/fj.201800742R

  10. Fan SH, Zhang ZF, Zheng YL, Lu J, Wu DM, Shan Q, et al. Troxerutin protects the mouse kidney from d-galactose-caused injury through anti-inflammation and anti-oxidation. Int Immunopharmacol 2009; 9: 91–6. doi: 10.1016/j.intimp.2008.10.008

  11. Shan Q, Zheng GH, Han XR, Wen X, Wang S, Li MQ, et al. Troxerutin protects kidney tissue against BDE-47-induced inflammatory damage through CXCR4-TXNIP/NLRP3 signaling. Oxid Med Cell Longev 2018; 2018: 9865495. doi: 10.1155/2018/9865495

  12. Zhang ZF, Shan Q, Zhuang J, Zhang YQ, Wang X, Fan SH, et al. Troxerutin inhibits 2,2’,4,4’-tetrabromodiphenyl ether (BDE-47)-induced hepatocyte apoptosis by restoring proteasome function. Toxicol Lett 2015; 233: 246–57. doi: 10.1016/j.toxlet.2015.01.017

  13. Sui R, Zang L, Bai Y. Administration of troxerutin and cerebroprotein hydrolysate injection alleviates cerebral ischemia/reperfusion injury by down-regulating caspase molecules. Neuropsychiatr Dis Treat 2019; 15: 2345–52. doi: 10.2147/NDT.S213212

  14. Xue X, Chen Y, Wang Y, Zhan J, Chen B, Wang X, et al. Troxerutin suppresses the inflammatory response in advanced glycation end-product-administered chondrocytes and attenuates mouse osteoarthritis development. Food Funct 2019; 10: 5059–69. doi: 10.1039/c9fo01089k

  15. Zamanian M, Bazmandegan G, Sureda A, Sobarzo-Sanchez E, Yousefi-Manesh H, Shirooie S. The protective roles and molecular mechanisms of troxerutin (vitamin P4) for the treatment of chronic diseases: a mechanistic review. Curr Neuropharmacol 2021; 19: 97–110. doi: 10.2174/1570159X18666200510020744

  16. Dehnamaki F, Karimi A, Pilevarian AA, Fatemi I, Hakimizadeh E, Kaeidi A, et al. Treatment with troxerutin protects against cisplatin-induced kidney injury in mice. Acta Chir Belg 2019; 119: 31–7. doi: 10.1080/00015458.2018.1455418

  17. Karwasra R, Kalra P, Gupta YK, Saini D, Kumar A, Singh, S. Antioxidant and anti-inflammatory potential of pomegranate rind extract to ameliorate cisplatin-induced acute kidney injury. Food Funct 2016; 7: 3091–101. doi: 10.1039/c6fo00188b

  18. Park MS, Leon MD, Devarajan P. Cisplatin induces apoptosis in LLC-PK1 cells via activation of mitochondrial pathways. J Am Soc Nephrol 2002; 13: 858–65. doi: 10.1681/ASN.V134858

  19. Wang Y, Liu Z, Shu S, Cai J, Tang C, Dong Z. AMPK/mTOR signaling in autophagy regulation during cisplatin-induced acute kidney injury. Front Physiol 2020; 11: 619730. doi: 10.3389/fphys.2020.619730

  20. Freitas-Lima LC, Budu A, Arruda AC, Perilhão MS, Barrera-Chimal J, Araujo RC, et al. PPAR-α deletion attenuates cisplatin nephrotoxicity by modulating renal organic transporters MATE-1 and OCT-2. Int J Mol Sci 2020; 21: 7416. doi: 10.3390/ijms21197416

  21. Katsuda H, Yamashita M, Katsura H, Yu J, Waki Y, Nagata N, et al. Protecting cisplatin-induced nephrotoxicity with cimetidine does not affect antitumor activity. Biol Pharm Bull 2010; 33: 1867–71. doi: 10.1248/bpb.33.1867

  22. Jiang S, Zhang H, Li X, Yi B, Huang L, Hu Z, et al. Vitamin D/VDR attenuate cisplatin-induced AKI by down-regulating NLRP3/Caspase-1/GSDMD pyroptosis pathway. J Steroid Biochem Mol Biol 2021; 206: 105789. doi: 10.1016/j.jsbmb.2020.105789

  23. Abo-Elmaaty AMA, Behairy A, El-Naseery NI, Abdel-Daim MM. The protective efficacy of vitamin E and cod liver oil against cisplatin-induced acute kidney injury in rats. Environ Sci Pollut Res Int 2020; 27: 44412–26. doi: 10.1007/s11356-020-10351-9

  24. Gao H, Wang X, Qu X, Zhai J, Tao L, Zhang Y, et al. Omeprazole attenuates cisplatin-induced kidney injury through suppression of the TLR4/NF-κB/NLRP3 signaling pathway. Toxicology 2020; 440: 152487. doi: 10.1016/j.tox.2020.152487

  25. Ye X, Ruan JW, Huang H, Huang WP, Zhang Y, Zhang F. PI3K-Akt-mTOR inhibition by GNE-477 inhibits renal cell carcinoma cell growth in vitro and in vivo. Aging (Albany NY) 2020; 12: 9489–99. doi: 10.18632/aging.103221

  26. Kanlaya R, Thongboonkerd V. Protective effects of epigallocatechin-3-gallate from green tea in various kidney diseases. Adv Nutr 2019; 10: 112–21. doi: 10.1093/advances/nmy077

  27. Jamali-Raeufy N, Kardgar S, Baluchnejadmojarad T, Roghani M, Goudarzi M. Troxerutin exerts neuroprotection against lipopolysaccharide (LPS) induced oxidative stress and neuroinflammation through targeting SIRT1/SIRT3 signaling pathway. Metab Brain Dis 2019; 34: 1505–13. doi: 10.1007/s11011-019-00454-9

  28. Sosa V, Moliné T, Somoza R, Paciucci R, Kondoh H, LLeonart ME. Oxidative stress and cancer: an overview. Ageing Res Rev 2013; 12: 376–90. doi: 10.1016/j.arr.2012.10.004

  29. Kaeidi A, Taghipour Z, Allahtavakoli M, Fatemi I, Hakimizadeh E, Hassanshahi J. Ameliorating effect of troxerutin in unilateral ureteral obstruction induced renal oxidative stress, inflammation, and apoptosis in male rats. Naunyn Schmiedebergs Arch Pharmacol 2020; 393: 879–88. doi: 10.1007/s00210-019-01801-4

  30. Chirino YI, Pedraza-Chaverri J. Role of oxidative and nitrosative stress in cisplatin-induced nephrotoxicity. Exp Toxicol Pathol 2009; 61: 223–42. doi: 10.1016/j.etp.2008.09.003

  31. Tadini-Buoninsegni F, Sordi G, Smeazzetto S, Natile G, Arnesano F. Effect of cisplatin on the transport activity of PII-type ATPases. Metallomics 2017; 9: 960–8. doi: 10.1039/c7mt00100b

  32. Holditch SJ, Brown CN, Lombardi AM, Nguyen KN, Edelstein CL. Recent advances in models, mechanisms, biomarkers, and interventions in cisplatin-induced acute kidney injury. Int J Mol Sci 2019; 20: 3011. doi: 10.3390/ijms20123011

  33. Hayden MS, Ghosh S. Regulation of NF-κB by TNF family cytokines. Semin Immunol 2014; 26: 253–66. doi: 10.1016/j.smim.2014.05.004

  34. Wang X, Gao Y, Wang L, Yang D, Bu W, Gou L, et al. Troxerutin improves dextran sulfate sodium-induced ulcerative colitis in mice. J Agric Food Chem 2021; 69: 2729–44. doi: 10.1021/acs.jafc.0c06755

  35. Badalzadeh R, Baradaran B, Alihemmati A, Yousefi B, Abbaszadeh A. Troxerutin preconditioning and ischemic postconditioning modulate inflammatory response after myocardial ischemia/reperfusion injury in rat model. Inflammation 2017; 40: 136–43. doi: 10.1007/s10753-016-0462-8

  36. Jafari-Khataylou Y, Emami SJ, Mirzakhani N. Troxerutin attenuates inflammatory response in lipopolysaccharide-induced sepsis in mice. Res Vet Sci 2021; 135: 469–78. doi: 10.1016/j.rvsc.2020.11.020

  37. Qi Z, Li W, Tan J, Wang C, Lin H, Zhou B, et al. Effect of ginsenoside Rh2 on renal apoptosis in cisplatin-induced nephrotoxicity in vivo. Phytomedicine 2019; 61: 152862. doi: 10.1016/j.phymed.2019.152862

  38. Dhanasekaran A, Gruenloh SK, Buonaccorsi JN, Zhang R, Gross GJ, Falck JR, et al. Multiple antiapoptotic targets of the PI3K/Akt survival pathway are activated by epoxyeicosatrienoic acids to protect cardiomyocytes from hypoxia/anoxia. Am J Physiol Heart Circ Physiol 2008; 294: H724–35. doi: 10.1152/ajpheart.00979.2007

  39. Su D, Zhou Y, Hu S, Guan L, Shi C, Wang Q, et al. Role of GAB1/PI3K/AKT signaling high glucose-induced cardiomyocyte apoptosis. Biomed Pharmacother 2017; 93: 1197–204. doi: 10.1016/j.biopha.2017.07.063

  40. Li Y, Xia J, Jiang N, Xian Y, Ju H, Wei Y, et al. Corin protects H2O2-induced apoptosis through PI3K/AKT and NF-κB pathway in cardiomyocytes. Biomed Pharmacother 2018; 97: 594–9. doi: 10.1016/j.biopha.2017.10.090

  41. Shu L, Zhang W, Huang C, Huang G, Su G. Troxerutin protects against myocardial ischemia/reperfusion injury via Pi3k/Akt pathway in rats. Cell Physiol Biochem 2017; 44: 1939–48. doi: 10.1159/000485884

  42. Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A 1975; 72: 1858–62. doi: 10.1073/pnas.72.5.1858

  43. Thapa N, Chen M, Horn HT, Choi S, Wen T, Anderson RA. Phosphatidylinositol-3-OH kinase signaling is spatially organized at endosomal compartments by microtubule-associated protein 4. Nat Cell Biol 2020; 22: 1357–70. doi: 10.1038/s41556-020-00596-4d

Published
2022-05-24
How to Cite
Guan T., Zheng Y., Jin S., Wang S., Hu M., Liu X., Huang S., & Liu Y. (2022). Troxerutin alleviates kidney injury in rats via PI3K/AKT pathway by enhancing MAP4 expression. Food & Nutrition Research, 66. https://doi.org/10.29219/fnr.v66.8469
Section
Original Articles