Skip to main content
SpringerLink
Log in

The Protective Effects of Vitamin B Complex on Diclofenac Sodium-Induced Nephrotoxicity: The Role of NOX4/RhoA/ROCK

  • RESEARCH
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Diclofenac sodium (DIC) is a widely used non-steroidal anti-inflammatory drug. Unfortunately, its prolonged use is associated with nephrotoxicity due to oxidative stress, inflammation, and fibrosis. We aimed to investigate the nephroprotective effects of vitamin B complex (B1, B6, B12) against DIC-induced nephrotoxicity and its impact on NOX4/RhoA/ROCK, a pathway that plays a vital role in renal pathophysiology. Thirty-two Wistar rats were divided into four groups: (1) normal control; (2) vitamin B complex (16 mg/kg B1, 16 mg/kg B6, 0.16 mg/kg B12, intraperitoneal); (3) DIC (10 mg/kg, intramuscular); and (4) DIC plus vitamin B complex group. After 14 days, the following were assayed: serum renal biomarkers (creatinine, blood urea nitrogen, kidney injury molecule-1), oxidative stress, inflammatory (tumor necrosis factor-α, interleukin-6), and fibrotic (transforming growth factor-β) markers as well as the protein levels of NOX4, RhoA, and ROCK. Structural changes, inflammatory cell infiltration, and fibrosis were detected using hematoxylin and eosin and Masson trichrome stains. Compared to DIC, vitamin B complex significantly decreased the renal function biomarkers, markers of oxidative stress and inflammation, and fibrotic cytokines. Glomerular and tubular damage, inflammatory infiltration, and excessive collagen accumulation were also reduced. Protein levels of NOX4, RhoA, and ROCK were significantly elevated by DIC, and this elevation was ameliorated by vitamin B complex. In conclusion, vitamin B complex administration could be a renoprotective approach during treatment with DIC via, at least in part, suppressing the NOX4/RhoA/ROCK pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data Availability

No datasets were generated or analyzed during the current study.

Abbreviations

BUN:

Blood urea nitrogen

COX:

Cyclooxygenase

DIC:

Diclofenac

GSH:

Reduced glutathione

H&E:

Hematoxylin and eosin

HRP:

Horseradish peroxidase

IL-6:

Interleukin-6

KIM-1:

Kidney injury molecule-1

KW/BW:

Kidney weight to body weight

MDA:

Malondialdehyde

NADPH:

Nicotinamide adenine dinucleotide phosphate

NOX4:

NADPH oxidase 4

NSAIDs:

Non-steroidal anti-inflammatory drugs

RhoA:

Ras homolog gene family member A

ROCK:

Rho-associated coiled-coil-forming protein kinase

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

TBA:

Thiobarbituric acid

TBS:

Tris-buffered saline

TGF-β:

Transforming growth factor-β

TNF-α:

Tumor necrosis factor-α

References

  1. Abiola, Tijani S., Oyindamola C. Adebayo, and O.O. Babalola. 2019. Diclofenac-induced kidney damage in wistar rats: Involvement of antioxidant mechanism. Journal of Biosciences and Medicines 07: 44–57. https://doi.org/10.4236/jbm.2019.712005.

    Article  CAS  Google Scholar 

  2. Hasan, Iman H., Amira Badr, Haneen Almalki, Alanoud Alhindi, and Hesham S. Mostafa. 2023. Podocin, mTOR, and CHOP dysregulation contribute to nephrotoxicity induced of lipopolysaccharide/diclofenac combination in rats: Curcumin and silymarin could afford protective effect. Life Sciences 330: 121996. https://doi.org/10.1016/j.lfs.2023.121996.

    Article  CAS  PubMed  Google Scholar 

  3. McGettigan, Patricia, and David Henry. 2005. Current problems with non-specific COX inhibitors. Current Pharmaceutical Design 6: 1693–1724. https://doi.org/10.2174/1381612003398690.

    Article  Google Scholar 

  4. Douros, Antonios, Elisabeth Bronder, Andreas Klimpel, Christiane Erley, Edeltraut Garbe, and Reinhold Kreutz. 2018. Drug-induced kidney injury: A large case series from the Berlin case-control surveillance study. Clinical Nephrology 89 (2018): 18–26. https://doi.org/10.5414/CN109212.

    Article  CAS  PubMed  Google Scholar 

  5. Cooper, Cyrus, Roland Chapurlat, Nasser Al-Daghri, Gabriel Herrero-Beaumont, Olivier Bruyère, François Rannou, Roland Roth, Daniel Uebelhart, and Jean-Yves. Reginster. 2019. Safety of oral non-selective non-steroidal anti-inflammatory drugs in osteoarthritis: What does the literature say? Drugs & Aging 36: 15–24. https://doi.org/10.1007/s40266-019-00660-1.

    Article  Google Scholar 

  6. Abdulmajeed, N.A., H.S. Alnahdi, N.O. Ayas, and A.M. Mohamed. 2015. Amelioration of cardiotoxic impacts of diclofenac sodium by vitamin B complex. European Review for Medical and Pharmacological Sciences 19: 671–681.

    CAS  PubMed  Google Scholar 

  7. Willis, J.V., M.J. Kendall, R.M. Flinn, D.P. Thornhill, and P.G. Welling. 1979. The pharmacokinetics of diclofenac sodium following intravenous and oral administration. European Journal of Clinical Pharmacology 16: 405–410. https://doi.org/10.1007/BF00568201.

    Article  CAS  PubMed  Google Scholar 

  8. Davies, N.M., and K.E. Anderson. 1997. Clinical pharmacokinetics of diclofenac. Therapeutic insights and pitfalls. Clinical Pharmacokinetics 33: 184–213. https://doi.org/10.2165/00003088-199733030-00003.

    Article  CAS  PubMed  Google Scholar 

  9. Alorabi, Mohammed, Simona Cavalu, Hayder M. Al-Kuraishy, Ali I. Al-Gareeb, Gomaa Mostafa-Hedeab, Walaa A. Negm, Amal Youssef, Aya H. El-Kadem, Hebatallah M. Saad, and Gaber El-Saber. Batiha. 2022. Pentoxifylline and berberine mitigate diclofenac-induced acute nephrotoxicity in male rats via modulation of inflammation and oxidative stress. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 152: 113225. https://doi.org/10.1016/j.biopha.2022.113225.

    Article  CAS  Google Scholar 

  10. Yasmeen, Talat, Ghulam Sarwar Qureshi, and Sughra Perveen. 2007. Adverse effects of diclofenac sodium on renal parenchyma of adult albino rats. JPMA. The Journal of the Pakistan Medical Association 57: 349–351.

    PubMed  Google Scholar 

  11. Alabi, Quadri K., and Rufus O. Akomolafe. 2020. Kolaviron Diminishes diclofenac-induced liver and kidney toxicity in wistar rats via suppressing inflammatory events, upregulating antioxidant defenses, and improving hematological indices. Dose-Response 18: 1–12. https://doi.org/10.1177/1559325819899256.

    Article  CAS  Google Scholar 

  12. Famurewa, Ademola C., Gabriel G. Akunna, Joseph Nwafor, Onyebuchi C. Chukwu, Chima A. Ekeleme-Egedigwe, and Janet N. Oluniran. 2020. Nephroprotective activity of virgin coconut oil on diclofenac-induced oxidative nephrotoxicity is associated with antioxidant and anti-inflammatory effects in rats. Avicenna Journal of Phytomedicine 10: 316–324.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Nouri, Ali, and Esfandiar Heidarian. 2019. Ameliorative effects of N-acetyl cysteine on diclofenac-induced renal injury in male rats based on serum biochemical parameters, oxidative biomarkers, and histopathological study. Journal of Food Biochemistry 43: e12950. https://doi.org/10.1111/jfbc.12950.

    Article  CAS  PubMed  Google Scholar 

  14. Samarija, Ita, and Ljubica Bubić-Filipi. 2008. Renal impairment induced by nonselective prostaglandin inhibitor. Acta Medica Croatica: Casopis Hravatske Akademije Medicinskih Znanosti 62: 461–467.

    PubMed  Google Scholar 

  15. Al-Kuraishy, Hayder M., Ali I. Al-Gareeb, and Nawar R. Hussien. 2019. Synergistic effect of berberine and pentoxifylline in attenuation of acute kidney injury. International Journal of Critical Illness and Injury Science 9: 69–74. https://doi.org/10.4103/IJCIIS.IJCIIS_85_18.

    Article  PubMed  PubMed Central  Google Scholar 

  16. van Swelm, Rachel P. L., Coby M. M. Laarakkers, Jeanne C. L. M. Pertijs, Vivienne Verweij, Rosalinde Masereeuw, and Frans G. M. Russel. 2013. Urinary proteomic profiling reveals diclofenac-induced renal injury and hepatic regeneration in mice. Toxicology and Applied Pharmacology 269: 141–149. https://doi.org/10.1016/j.taap.2013.03.005.

    Article  CAS  PubMed  Google Scholar 

  17. Meng, Xiao-Ming., Gui-Ling. Ren, Li. Gao, Qin Yang, Hai-Di. Li, Wu. Wei-Feng, Cheng Huang, Lei Zhang, Xiong-Wen. Lv, and Jun Li. 2018. NADPH oxidase 4 promotes cisplatin-induced acute kidney injury via ROS-mediated programmed cell death and inflammation. Laboratory Investigation; a Journal of Technical Methods and Pathology 98: 63–78. https://doi.org/10.1038/labinvest.2017.120.

    Article  CAS  PubMed  Google Scholar 

  18. Sedeek, Mona, Rania Nasrallah, Rhian M. Touyz, and Richard L. Hébert. 2013. NADPH oxidases, reactive oxygen species, and the kidney: Friend and foe. Journal of the American Society of Nephrology: JASN 24: 1512–1518. https://doi.org/10.1681/ASN.2012111112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Seccia, Teresa M., Matteo Rigato, Verdiana Ravarotto, and Lorenzo A. Calò. 2020. ROCK (RhoA/Rho kinase) in cardiovascular-renal pathophysiology: A review of new advancements. Journal of Clinical Medicine 9: 1328. https://doi.org/10.3390/jcm9051328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Feng, Yangbo, Philip V. LoGrasso, Olivier Defert, and Rongshi Li. 2016. Rho kinase (ROCK) inhibitors and their therapeutic potential. Journal of Medicinal Chemistry 59: 2269–2300. https://doi.org/10.1021/acs.jmedchem.5b00683.

    Article  CAS  PubMed  Google Scholar 

  21. Kolavennu, Vasantha, Lixia Zeng, Hui Peng, Yin Wang, and Farhad R. Danesh. 2008. Targeting of RhoA/ROCK signaling ameliorates progression of diabetic nephropathy independent of glucose control. Diabetes 57: 714–723. https://doi.org/10.2337/db07-1241.

    Article  CAS  PubMed  Google Scholar 

  22. Shi, Jianjian, and Lei Wei. 2007. Rho kinase in the regulation of cell death and survival. Archivum Immunologiae Et Therapiae Experimentalis 55: 61–75. https://doi.org/10.1007/s00005-007-0009-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gómez, Gonzalo I., Victoria Velarde, and Juan C. Sáez. 2019. Role of a RhoA/ROCK-dependent pathway on renal Connexin43 regulation in the angiotensin II-induced renal damage. International Journal of Molecular Sciences 20: 4408. https://doi.org/10.3390/ijms20184408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jihua, Chen, Chen Cai, Bao Xubin, and Yu. Yue. 2020. Effects of dexmedetomidine on the RhoA /ROCK/ Nox4 signaling pathway in renal fibrosis of diabetic rats. Open Medicine (Poland) 14: 890–898. https://doi.org/10.1515/med-2019-0105.

    Article  CAS  Google Scholar 

  25. Manickam, Nagaraj, Mandakini Patel, Kathy K. Griendling, Yves Gorin, and Jeffrey L. Barnes. 2014. RhoA/Rho kinase mediates TGF-β1-induced kidney myofibroblast activation through Poldip2/Nox4-derived reactive oxygen species. American Journal of Physiology. Renal Physiology 307: F159-171. https://doi.org/10.1152/ajprenal.00546.2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xie, Xi., Xiuting Chang, Lei Chen, Kaipeng Huang, Juan Huang, Shaogui Wang, Xiaoyan Shen, Peiqing Liu, and Heqing Huang. 2013. Berberine ameliorates experimental diabetes-induced renal inflammation and fibronectin by inhibiting the activation of RhoA/ROCK signaling. Molecular and Cellular Endocrinology 381: 56–65. https://doi.org/10.1016/j.mce.2013.07.019.

    Article  CAS  PubMed  Google Scholar 

  27. Babelova, Andrea, Felix Jansen, Kerstin Sander, Matthias Löhn, Liliana Schäfer, Christian Fork, Hartmut Ruetten, et al. 2013. Activation of Rac-1 and RhoA contributes to podocyte injury in chronic kidney disease. PLoS ONE 8: e80328. https://doi.org/10.1371/journal.pone.0080328.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mandić, Marija, Katarina Mitić, Predrag Nedeljković, Mina Perić, Bojan Božić, Tanja Lunić, Ana Bačić, Mirjana Rajilić-Stojanović, Sanja Peković, and Biljana Božić Nedeljković. 2022. Vitamin B complex and experimental autoimmune encephalomyelitis -attenuation of the clinical signs and gut microbiota dysbiosis. Nutrients 14: 1273. https://doi.org/10.3390/nu14061273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ford, Talitha C., Luke A. Downey, Tamara Simpson, Grace McPhee, Chris Oliver, and Con Stough. 2018. The effect of a high-dose vitamin b multivitamin supplement on the relationship between brain metabolism and blood biomarkers of oxidative stress: A randomized control trial. Nutrients 10: 1860. https://doi.org/10.3390/nu10121860.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lindschinger, Meinrad, Franz Tatzber, Wolfgang Schimetta, Irene Schmid, Barbara Lindschinger, Gerhard Cvirn, Olaf Stanger, Eugenia Lamont, and Willibald Wonisch. 2019. A randomized pilot trial to evaluate the bioavailability of natural versus synthetic vitamin b complexes in healthy humans and their effects on homocysteine, oxidative stress, and antioxidant levels. Oxidative Medicine and Cellular Longevity 2019: 6082613. https://doi.org/10.1155/2019/6082613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ullegaddi, Rajesh, Hilary J. Powers, and Salah E. Gariballa. 2004. B-group vitamin supplementation mitigates oxidative damage after acute ischaemic stroke. Clinical Science (London, England: 1979) 107: 477–484. https://doi.org/10.1042/CS20040134.

    Article  CAS  PubMed  Google Scholar 

  32. Ullegaddi, Rajesh, Hilary J. Powers, and Salah E. Gariballa. 2006. Antioxidant supplementation with or without B-group vitamins after acute ischemic stroke: A randomized controlled trial. JPEN. Journal of parenteral and enteral nutrition 30: 108–114. https://doi.org/10.1177/0148607106030002108.

    Article  CAS  PubMed  Google Scholar 

  33. Calderon-Ospina, Carlos-Alberto., Mauricio Orlando Nava-Mesa, and Carlos Emilio Arbeláez. Ariza. 2020. Effect of combined diclofenac and B vitamins (thiamine, pyridoxine, and cyanocobalamin) for low back pain management: systematic review and meta-analysis. Pain Medicine (Malden, Mass) 21: 766–781. https://doi.org/10.1093/pm/pnz216.

    Article  PubMed  Google Scholar 

  34. Rocha-González, Héctor. I., Flavio Terán-Rosales, Gerardo Reyes-García, Roberto Medina-Santillán, and Vinicio Granados-Soto. 2004. B vitamins increase the analgesic effect of diclofenac in the rat. Proceedings of the Western Pharmacology Society 47: 84–87.

    PubMed  Google Scholar 

  35. Al-Kharashi, L., H. Attia, A. Alsaffi, T. Almasri, M. Arafa, I. Hasan, H. Alajami, R. Ali, and A. Badr. 2023. Pentoxifylline and thiamine ameliorate rhabdomyolysis-induced acute kidney injury in rats via suppressing TLR4/NF-κB and NLRP-3/caspase-1/gasdermin mediated-pyroptosis. Toxicology and Applied Pharmacology. https://doi.org/10.1016/j.taap.2023.116387.

    Article  PubMed  Google Scholar 

  36. Latif, Amera Abd, Doaa H. El, Ebtihal M. Assar, Hanafy A. Elkaw, Dalal Hussien Hamza, M. Alkhalifah, Wael N. Hozzein, and Ragaa A. Hamouda. 2021. Protective role of Chlorella vulgaris with thiamine against paracetamol induced toxic effects on haematological, biochemical, oxidative stress parameters and histopathological changes in Wistar rats. Scientific Reports 11: 3911. https://doi.org/10.1038/s41598-021-83316-8.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  37. Alshanwani, Aliah R., Azza M. Mohamed, Laila M. Faddah, Sameerah Shaheen, Maha M. Arafah, Hanan Hagar, Ahlam M. Alhusaini, Fatima M. B. Alharbi, Alaa AlHarthii, and Amira M. Badr. 2021. Cyanocobalamin and/or calcitriol mitigate renal damage-mediated by tamoxifen in rats: Implication of caspase-3/NF-κB signaling pathways. Life Sciences 277: 119512. https://doi.org/10.1016/j.lfs.2021.119512.

    Article  CAS  PubMed  Google Scholar 

  38. Hajihashemi, Saeed, Zeinab Hamidizad, Ali Rahbari, Fatemeh Ghanbari, and Zohre Aghaee Motealeghi. 2017. Effects of cobalamin (vitamin b12) on gentamicin induced nephrotoxicity in rat. Drug Research 67: 710–718. https://doi.org/10.1055/s-0043-117418.

    Article  CAS  PubMed  Google Scholar 

  39. Wang, Ying, Ying Li, Zhiping Yang, Ziqiang Wang, Jiang Chang, Tao Zhang, Yanqing Chi, Ning Han, and Kunxiao Zhao. 2019. Pyridoxamine treatment of HK-2 human proximal tubular epithelial cells reduces oxidative stress and the inhibition of autophagy induced by high glucose levels. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research 25: 1480–1488. https://doi.org/10.12659/MSM.914799.

    Article  PubMed  Google Scholar 

  40. Kopruszinski, Caroline M., Renata C. Reis, Elisangela Bressan, Peter W. Reeh, and Juliana G. Chichorro. 2015. Vitamin B complex attenuated heat hyperalgesia following infraorbital nerve constriction in rats and reduced capsaicin in vivo and in vitro effects. European Journal of Pharmacology 762: 326–332. https://doi.org/10.1016/j.ejphar.2015.05.063.

    Article  CAS  PubMed  Google Scholar 

  41. Dogra, Ashish, Dilpreet Kour, Abhishek Gour, Mahir Bhardwaj, Swarnendu Bag, Shakti Kumar Dhiman, Ajay Kumar, Gurdarshan Singh, and Utpal Nandi. 2023. Ameliorating effect of rutin against diclofenac-induced cardiac injury in rats with underlying function of FABP3, MYL3, and ANP. Drug and Chemical Toxicology 46: 597–608. https://doi.org/10.1080/01480545.2022.2069804.

    Article  CAS  PubMed  Google Scholar 

  42. Nouri, Ali, Farzad Izak-Shirian, Vahideh Fanaei, Maryam Dastan, Mahdieh Abolfathi, Alireza Moradi, Mansoor Khaledi, and Hamzeh Mirshekari-Jahangiri. 2021. Carvacrol exerts nephroprotective effect in rat model of diclofenac-induced renal injury through regulation of oxidative stress and suppression of inflammatory response. Heliyon 7: e08358. https://doi.org/10.1016/j.heliyon.2021.e08358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ohkawa, H., N. Ohishi, and K. Yagi. 1979. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical Biochemistry 95: 351–358. https://doi.org/10.1016/0003-2697(79)90738-3.

    Article  CAS  PubMed  Google Scholar 

  44. Ellman, G.L., and H. Lysko. 1967. Disulfide and sulfhydryl compounds in TCA extracts of human blood and plasma. The Journal of Laboratory and Clinical Medicine 70: 518–527.

    CAS  PubMed  Google Scholar 

  45. Minami, M., and H. Yoshikawa. 1979. A simplified assay method of superoxide dismutase activity for clinical use. Clin ChimActa 92 (3): 337–42. https://doi.org/10.1016/0009-8981(79)90211-0.

    Article  CAS  Google Scholar 

  46. Sathishkumar, Palanivel, Kannan Mohan, Ramakrishnan Anu Alias. Meena, Murugesan Balasubramanian, Loganathan Chitra, Abirami Ramu Ganesan, Thayumanavan Palvannan, Satinder Kaur Brar, and Gu. Feng Long. 2021. Hazardous impact of diclofenac on mammalian system: Mitigation strategy through green remediation approach. Journal of Hazardous Materials 419 Elsevier: 126135.

    Article  CAS  PubMed  Google Scholar 

  47. Ogle, C. 1989. Diclofenac. Connecticut Medicine 53: 603–604.

    CAS  PubMed  Google Scholar 

  48. Shield, M.J. 1998. Diclofenac/misoprostol: Novel findings and their clinical potential. The Journal of Rheumatology 51: 31–41.

    CAS  PubMed  Google Scholar 

  49. Fattori, Victor, Sergio M. Borghi, Carla F.S.. Guazelli, Andressa C. Giroldo, Jefferson Crespigio, Allan J.C.. Bussmann, Letícia Coelho-Silva, et al. 2017. Vinpocetine reduces diclofenac-induced acute kidney injury through inhibition of oxidative stress, apoptosis, cytokine production, and NF-κB activation in mice. Pharmacological Research 120 Elsevier Ltd: 10–22. https://doi.org/10.1016/j.phrs.2016.12.039.

    Article  CAS  PubMed  Google Scholar 

  50. Gounden V, Bhatt H, Jialal I. Renal Function Tests. 2023 Jul 17. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024. PMID: 29939598

  51. Ustuner, Mehmet Alperen, Dilara Kaman, and Neriman Colakoglu. 2017. Effects of benfotiamine and coenzyme Q10 on kidney damage induced gentamicin. Tissue & Cell 49: 691–696. https://doi.org/10.1016/j.tice.2017.10.001.

    Article  CAS  Google Scholar 

  52. Harisa, Gamaleldin I. 2013. Benfotiamine enhances antioxidant defenses and protects against cisplatin-induced DNA damage in nephrotoxic rats. Journal of Biochemical and Molecular Toxicology 27: 398–405. https://doi.org/10.1002/jbt.21501.

    Article  ADS  CAS  PubMed  Google Scholar 

  53. Güneş, Ali, Fesih Aktar, İlhan Tan, Murat Söker, Ünal. Uluca, Hasan Balık, and Nuriye Mete. 2016. Urinary levels of early kidney injury molecules in children with vitamin B12 deficiency. Archivos Argentinos De Pediatria 114: 453–457. https://doi.org/10.5546/aap.2016.eng.453.

    Article  PubMed  Google Scholar 

  54. Nishikawa, T., D. Edelstein, and M. Brownlee. 2000. The missing link: A single unifying mechanism for diabetic complications. Kidney International. Supplement 77: S26-30. https://doi.org/10.1046/j.1523-1755.2000.07705.x.

    Article  CAS  PubMed  Google Scholar 

  55. Peter, S.J., and S.E. Prince. 2018. Diclofenac-induced renal toxicity in female Wistar albino rats is protected by the pre-treatment of aqueous leaves extract of Madhuca longifolia through suppression of inflammation, oxidative stress and cytokine formation. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 98: 45–51. https://doi.org/10.1016/j.biopha.2017.12.028.

    Article  CAS  Google Scholar 

  56. Enriquez, J.I., M. Schydlower, K.C. O’Hair, R.C. Keniston, M.A. Nadjem, and I. Delgado. 1992. Effect of vitamin B6 supplementation on gentamicin nephrotoxicity in rabbits. Veterinary and Human Toxicology 34: 32–35.

    CAS  PubMed  Google Scholar 

  57. Li, Feng, Edward M. Bahnson, Jennifer Wilder, Robin Siletzky, John Hagaman, Volker Nickekeit, Sylvia Hiller, et al. 2020. Oral high dose vitamin B12 decreases renal superoxide and post-ischemia/reperfusion injury in mice. Redox Biology 32: 101504. https://doi.org/10.1016/j.redox.2020.101504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Torres-González, Liliana, Eduardo Cienfuegos-Pecina, Marlene M. Perales-Quintana, Gabriela Alarcon-Galvan, Linda E. Muñoz-Espinosa, Edelmiro Pérez-Rodríguez, and Paula Cordero-Pérez. 2018. Nephroprotective effect of Sonchus oleraceus extract against kidney injury induced by ischemia-reperfusion in Wistar rats. Oxidative Medicine and Cellular Longevity. https://doi.org/10.1155/2018/9572803.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Alshukri, Harith Abdelelah, Mazin Hadi Kzar, and Aied Kareem Abdaun. 2021. Measurement of GSH, SOD and MDA some antioxidant level after excises athletes. Indian Journal of Forensic Medicine and Toxicology 15: 2539–2546. https://doi.org/10.37506/ijfmt.v15i1.13782.

    Article  CAS  Google Scholar 

  60. Ratliff, Brian B., Wasan Abdulmahdi, Rahul Pawar, and Michael S. Wolin. 2016. Oxidant mechanisms in renal injury and disease. Antioxidants and Redox Signaling 25: 119–146. https://doi.org/10.1089/ars.2016.6665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Berger, Mette M., and René L. Chioléro. 2007. Antioxidant supplementation in sepsis and systemic inflammatory response syndrome. Critical Care Medicine. https://doi.org/10.1097/01.CCM.0000279189.81529.C4.

    Article  PubMed  Google Scholar 

  62. Misra, Usha Kant, Jayantee Kalita, Sandeep Kumar Singh, and Sushil Kumar Rahi. 2017. Oxidative stress markers in vitamin B12 deficiency. Molecular Neurobiology 54: 1278–1284. https://doi.org/10.1007/s12035-016-9736-2.

    Article  CAS  PubMed  Google Scholar 

  63. Guemouri, L., Y. Artur, B. Herbeth, C. Jeandel, G. Cuny, and G. Siest. 1991. Biological variability of superoxide dismutase, glutathione peroxidase, and catalase in blood. Clinical Chemistry 37: 1932–1937. https://doi.org/10.1093/clinchem/37.11.1932.

    Article  CAS  PubMed  Google Scholar 

  64. Ungprasert, Patompong, Wisit Cheungpasitporn, Cynthia S. Crowson, and Eric L. Matteson. 2015. Individual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: A systematic review and meta-analysis of observational studies. European Journal of Internal Medicine 26: 285–291. https://doi.org/10.1016/j.ejim.2015.03.008.

    Article  CAS  PubMed  Google Scholar 

  65. Lonappan, L., S.K. Brar, R.K. Das, M. Verma, and R.Y. Surampalli. 2016. Diclofenac and its transformation products: Environmental occurrence and toxicity - A review. Environ Int 96: 127–138. https://doi.org/10.1016/j.envint.2016.09.014. Epub 2016 Sep 17.

    Article  CAS  PubMed  Google Scholar 

  66. Higashi-Okai, Kiyoka, Harumi Nagino, Kaori Yamada, and Yasuji Okai. 2006. Antioxidant and prooxidant activities of B group vitamins in lipid peroxidation. Journal of UOEH 28: 359–368. https://doi.org/10.7888/juoeh.28.359.

    Article  CAS  PubMed  Google Scholar 

  67. Balk, E., M. Chung, G. Raman, A. Tatsioni, P. Chew, S. Ip, D. DeVine, and J. Lau. 2006. B vitamins and berries and age-relatedneurodegenerative disorders. Evid Rep Technol Assess (Full Rep) 134: 1–161 PMID: 17628125;PMCID: PMC4781311.

    Google Scholar 

  68. Mahfouz, M.M., and F.A. Kummerow. 2004. Vitamin C or Vitamin B6 supplementation prevent the oxidative stress and decrease of prostacyclin generation in homocysteinemic rats. The International Journal of Biochemistry & Cell Biology 36: 1919–1932. https://doi.org/10.1016/j.biocel.2004.01.028.

    Article  CAS  Google Scholar 

  69. Moreira, Edward S., Nicola E. Brasch, and June Yun. 2011. Vitamin B12 protects against superoxide-induced cell injury in human aortic endothelial cells. Free Radical Biology & Medicine 51: 876–883. https://doi.org/10.1016/j.freeradbiomed.2011.05.034.

    Article  CAS  Google Scholar 

  70. Rakić, Marija, Tanja Lunić, Marina Bekić, Sergej Tomić, Katarina Mitić, Stefan Graovac, Bojan Božić, and Biljana Božić Nedeljković. 2023. Vitamin B complex suppresses neuroinflammation in activated microglia: In vitro and in silico approach combined with dynamical modeling. International Immunopharmacology 121: 110525. https://doi.org/10.1016/j.intimp.2023.110525.

    Article  CAS  PubMed  Google Scholar 

  71. Hussain, Tarique, Bie Tan, Yulong Yin, Francois Blachier, Myrlene C. B. Tossou, and Najma Rahu. 2016. Oxidative stress and inflammation: What polyphenols can do for us? Oxidative Medicine and Cellular Longevity 2016: 7432797. https://doi.org/10.1155/2016/7432797.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Anderson, Michael T., Frank J.T.. Staal, Carlos Gitler, Leonard A. Herzenberg, and Leonore A. Herzenberg. 1994. Separation of oxidant-initiated and redox-regulated steps in the NF-κB signal transduction pathway. Proceedings of the National Academy of Sciences of the United States of America 91: 11527–11531. https://doi.org/10.1073/pnas.91.24.11527.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gu, Yue Yu, Xu Sheng Liu, Xiao Ru Huang, Yu. Xue Qing, and Hui Yao Lan. 2020. Diverse role of TGF-β in kidney disease. Frontiers in Cell and Developmental Biology 8: 1–13. https://doi.org/10.3389/fcell.2020.00123.

    Article  Google Scholar 

  74. Meng, Xiao Ming, David J. Nikolic-Paterson, and Hui Yao Lan. 2016. TGF-β: The master regulator of fibrosis. Nature Reviews Nephrology 12: 325–338. Nature Publishing Group. https://doi.org/10.1038/nrneph.2016.48. 

    Article  CAS  PubMed  Google Scholar 

  75. Ghaiad, Heba R., Shimaa O. Ali, Asmaa K. Al-Mokaddem, and Maha Abdelmonem. 2023. Regulation of PKC/TLR-4/NF-kB signaling by sulbutiamine improves diabetic nephropathy in rats. Chemico-Biological Interactions 381: 110544. https://doi.org/10.1016/j.cbi.2023.110544.

    Article  CAS  PubMed  Google Scholar 

  76. Menezes, Raquel R., Adriana M. Godin, Felipe Fernandes Rodrigues, Giovanna M. E. Coura, Ivo S. F. Melo, Mercy S. Ana, Caryne M. Brito, Bertollo, et al. 2017. Thiamine and riboflavin inhibit production of cytokines and increase the anti-inflammatory activity of a corticosteroid in a chronic model of inflammation induced by complete Freund’s adjuvant. Pharmacological reports: PR 69: 1036–1043. https://doi.org/10.1016/j.pharep.2017.04.011.

    Article  CAS  PubMed  Google Scholar 

  77. Elseweidy, Mohamed M., Sahar E. Elswefy, Nahla N. Younis, and Mohamed S. Zaghloul. 2013. Pyridoxamine, an inhibitor of protein glycation, in relation to microalbuminuria and proinflammatory cytokines in experimental diabetic nephropathy. Experimental Biology and Medicine (Maywood, N. J.) 238: 881–888. https://doi.org/10.1177/1535370213494644.

    Article  CAS  PubMed  Google Scholar 

  78. Aycan, İlker Öngüç., Özlem. Elpek, Bahar Akkaya, Ebru Kıraç, Hazal Tuzcu, Sabriye Kaya, Nesil Coşkunfırat, and Mutay Aslan. 2018. Diclofenac induced gastrointestinal and renal toxicity is alleviated by thymoquinone treatment. Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association 118: 795–804. https://doi.org/10.1016/j.fct.2018.06.038.

    Article  CAS  PubMed  Google Scholar 

  79. Alshanwani, A.R., H. Hagar, S. Shaheen, A.M. Alhusaini, M.M. Arafah, L.M. Faddah, F.M. Alharbi, A.K. Sharma, A. Fayed, and A.M. Badr. 2022. A promising antifibrotic drug, pyridoxamine attenuates thioacetamide-induced liver fibrosis by combating oxidative stress, advanced glycation end products, and balancing matrix metalloproteinases. European Journal of Pharmacology. https://doi.org/10.1016/j.ejphar.2022.174910.

    Article  PubMed  Google Scholar 

  80. Ahmad, A., N. Afroz, U.D. Gupta, and R. Ahmad. 2014. Vitamin B12 supplement alleviates N’-nitrosodimethylamine-induced hepatic fibrosis in rats. Pharmaceutical Biology. https://doi.org/10.3109/13880209.2013.864682.

    Article  PubMed  Google Scholar 

  81. Zhang, Huimin, Fangfang Lai, Xi. Cheng, and Yu. Wang. 2023. Involvement of NADPH oxidases in the Na/K-ATPase/Src/ROS oxidant amplification loop in renal fibrosis. Molecular Medicine Reports 28: 161. https://doi.org/10.3892/mmr.2023.13048.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Zhou, Baoshang, Mu. Jiao, Yi. Gong, Lu. Caibao, Youguang Zhao, Ting He, and Zhexue Qin. 2017. Brd4 inhibition attenuates unilateral ureteral obstruction-induced fibrosis by blocking TGF-β-mediated Nox4 expression. Redox Biology 11 Elsevier B.V: 390–402.

    Article  CAS  PubMed  Google Scholar 

  83. Babelova, Andrea, Despina Avaniadi, Oliver Jung, Christian Fork, Janet Beckmann, Judith Kosowski, Norbert Weissmann, et al. 2012. Role of Nox4 in murine models of kidney disease. Free Radical Biology and Medicine 53: 842–853. https://doi.org/10.1016/j.freeradbiomed.2012.06.027.

    Article  CAS  PubMed  Google Scholar 

  84. Hecker, Louise, Ragini Vittal, Tamara Jones, Rajesh Jagirdar, Tracy R. Luckhardt, Jeffrey C. Horowitz, Subramaniam Pennathur, Fernando J. Martinez, and Victor J. Thannickal. 2009. NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nature Medicine 15: 1077–1081. Nature Publishing Group. https://doi.org/10.1038/nm.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Barnes, Jeffrey L., and Yves Gorin. 2011. Myofibroblast differentiation during fibrosis Role of NAD(P)H oxidases. Kidney International 79 Elsevier Masson SAS: 944–956. https://doi.org/10.1038/ki.2010.516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Xiang, Chengyu, Yi. Yan, and Dingguo Zhang. 2021. Alleviation of the doxorubicin-induced nephrotoxicity by fasudil in vivo and in vitro. Journal of Pharmacological Sciences 145: 6–15. https://doi.org/10.1016/j.jphs.2020.10.002.

    Article  CAS  PubMed  Google Scholar 

  87. Su, Jinzi, Wenbo Zou, Wenqin Cai, Xiuping Chen, Fangbing Wang, Shuizhu Li, Wenwen Ma, and Yangming Cao. 2014. Atorvastatin ameliorates contrast medium-induced renal tubular cell apoptosis in diabetic rats via suppression of Rho-kinase pathway. European Journal of Pharmacology 723: 15–22. https://doi.org/10.1016/j.ejphar.2013.10.025.

    Article  CAS  PubMed  Google Scholar 

  88. Liu, Li-Juan., Feng-Juan. Yao, Lu. Gui-Hua, Xu. Cheng-Gui, Xu. Zhe, Kai Tang, Yun-Jiu. Cheng, Xiu-Ren. Gao, and Wu. Su-Hua. 2016. The role of the Rho/ROCK pathway in Ang II and TGF-β1-induced atrial remodeling. PLoS ONE 11: e0161625. https://doi.org/10.1371/journal.pone.0161625.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Xie, Y., T. Song, M. Huo, Y. Zhang, Y.-Y. Zhang, Z.-H. Ma, N. Wang, J.-P. Zhang, and L. Chu. 2018. Fasudil alleviates hepatic fibrosis in type 1 diabetic rats: involvement of the inflammation and RhoA/ROCK pathway. European Review for Medical and Pharmacological Sciences 22: 5665–5677. https://doi.org/10.26355/eurrev_201809_15834.

    Article  CAS  PubMed  Google Scholar 

  90. Chiazza, F., A.S. Cento, D. Collotta, D. Nigro, G. Rosa, F. Baratta, V. Bitonto, et al. 2017. Protective effects of pyridoxamine supplementation in the early stages of diet-induced kidney dysfunction. BioMed Research International 2017: 2682861. https://doi.org/10.1155/2017/2682861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The authors extend their appreciation to the Deputyship for Research and Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project no. (IFKSUOR3-154-2).

Author information

Author notes

  1. Hala Attia and Amira Badr equally contributed to the work.

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P. O. Box: 2454, Riyadh, 11495, Saudi Arabia

    Hala Attia, Amira Badr, Samiyah Alshehri, Iman Hasan & Rehab Ali

  2. College of Pharmacy, King Saud University, Riyadh, 11495, Saudi Arabia

    Orjuwan Alshehri & Waad Alsulaiman

  3. Department of Physiology, College of Medicine, King Saud University, Riyadh, 11495, Saudi Arabia

    Aliah Alshanwani

  4. Pathology Department, College of Medicine, King Saud University, Riyadh, 11495, Saudi Arabia

    Maha Arafa

Authors
  1. Hala Attia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amira Badr
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Orjuwan Alshehri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Waad Alsulaiman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aliah Alshanwani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Samiyah Alshehri
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maha Arafa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Iman Hasan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rehab Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization and study design: H.A., O.A., and W.A.. All authors contribute to methodology, investigation and data collection. Formal analysis: H.A., O.A., and W.A. Supervision: H.A. and A. B., Funding acquisition: H.A. and A. A. Project administration: H.A. and A. B., Writing: Original Draft: H.A., A. B. and S.A., Writing: Review and Editing: H.A. and A.B. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Hala Attia.

Ethics declarations

Ethics Approval

All animal experiments were carried out in accordance with U.K. Animals Act, 1986 and associated guidelines. The study design and all experimental procedures were approved by the Research Ethics Committee at King Saud University (Approval No: KSU-SE-22-79).

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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Attia, H., Badr, A., Alshehri, O. et al. The Protective Effects of Vitamin B Complex on Diclofenac Sodium-Induced Nephrotoxicity: The Role of NOX4/RhoA/ROCK. Inflammation (2024). https://doi.org/10.1007/s10753-024-01996-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10753-024-01996-6

Keywords

Search

Navigation