Tranilast protects from sepsis-induced acute kidney injury in rat via the STAT-3 signaling pathway

Year 2025, Volume: 11 Issue: 6, 1043 - 1056

Mümin Alper Erdoğan , Arife Erdoğan , Oytun Erbaş

https://doi.org/10.18621/eurj.1701524

Abstract

Objectives: Sepsis-induced acute kidney injury (SI-AKI) is a major contributor to morbidity and mortality among critically ill patients. This experimental study evaluated the renoprotective effects of Tranilast, an anti-inflammatory and antifibrotic agent, in a rat model of polymicrobial sepsis, with a focus on modulation of the signal transducer and activator of transcription 3 (STAT-3) signaling pathway.

Methods: Thirty-six female Wistar albino rats were randomly assigned to three groups: Sham control, cecal ligation and puncture (CLP)+saline, and CLP+Tranilast (300 mg/kg/day). Sepsis was induced by CLP. Survival was monitored for five days. Biochemical parameters including plasma tumor necrosis factor alpha (TNF-α), neutrophil gelatinase-associated lipocalin (NGAL), heat shock protein 27 (HSP-27), malondialdehyde (MDA), blood urea nitrogen (BUN), and renal STAT-3 expression were assessed via ELISA and spectrophotometric assays. Histopathological evaluation of renal tissues was performed to assess tubular injury, inflammation, and hemorrhage. Results are expressed as mean±standard error of the mean (SEM).

Results: Tranilast significantly improved survival in septic rats (75% vs. 50% in CLP+saline), reduced plasma MDA and TNF-α levels, lowered BUN and NGAL concentrations, and suppressed renal STAT-3 expression (P<0.05). It also enhanced HSP-27 levels, suggesting activation of cytoprotective responses. Histological analysis demonstrated reduced tubular necrosis, luminal debris, inflammation, and hemorrhage in Tranilast-treated rats.

Conclusions: Tranilast provides significant renoprotection in SI-AKI by reducing oxidative stress, inflammation, and STAT-3 activity while enhancing cytoprotective mechanisms. These findings support its potential as an adjunctive therapeutic agent for managing sepsis-related organ injury.

Keywords

Sepsis , akut kidney injury , tranilast , STAT-3 pathway , oxidative stress , inflammation

Ethical Statement

The study protocol was reviewed and approved by the Demiroğlu Science University Animal Experiments Local Ethics Committee (HADYEK) (Decision No: 0825015107; date: 15.02.2023). All experimental procedures involving animals were conducted in accordance with the ethical standards of the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health. All efforts were made to minimize animal suffering and to reduce the number of animals used.

References

• 1. Peerapornratana S, Manrique-Caballero CL, Gómez H, Kellum JA. Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney Int. 2019;96(5):1083-1099. doi: 10.1016/j.kint.2019.05.026.
• 2. Zarbock A, Gomez H, Kellum JA. Sepsis-induced acute kidney injury revisited: pathophysiology, prevention and future therapies. Curr Opin Crit Care. 2014;20(6):588-595. doi: 10.1097/MCC.0000000000000153.
• 3. Gomez H, Ince C, De Backer D, et al. A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury. Shock. 2014;41(1):3-11. doi: 10.1097/SHK.0000000000000052.
• 4. Hubbard WJ, Choudhry M, Schwacha MG, et al. Cecal ligation and puncture. Shock. 2005;24 Suppl 1:52-57. doi: 10.1097/01.shk.0000191414.94461.7e.
• 5. Schrier RW, Wang W. Acute renal failure and sepsis. N Engl J Med. 2004;351(2):159-169. doi: 10.1056/NEJMra032401.
• 6. Mishra J, Ma Q, Prada A, et al. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol. 2003;14(10):2534-2543. doi: 10.1097/01.asn.0000088027.54400.c6.
• 7. Golan-Lagziel T, Lewis YE, Shkedi O, Douvdevany G, Caspi LH, Kehat I. Analysis of rat cardiac myocytes and fibroblasts identifies combinatorial enhancer organization and transcription factor families. J Mol Cell Cardiol. 2018;116:91-105. doi: 10.1016/j.yjmcc.2018.02.003.
• 8. Tan Z, Liu Q, Chen H, et al. Pectolinarigenin alleviated septic acute kidney injury via inhibiting Jak2/Stat3 signaling and mitochondria dysfunction. Biomed Pharmacother. 2023;159:114286. doi: 10.1016/j.biopha.2023.114286.
• 9. Hiratochi M, Takamoto M, Tatemichi S, Sugane K. Inhibition of interleukin 5 production with no influence on interleukin 4 production by an anti-allergic drug, tranilast, in Toxocara canis-infected mice. Int J Immunopharmacol. 2000;22(6):463-471. doi: 10.1016/s0192-0561(00)00013-8.
• 10. Lee H, Jeong AJ, Ye SK. Highlighted STAT3 as a potential drug target for cancer therapy. BMB Rep. 2019;52(7):415-423. doi: 10.5483/BMBRep.2019.52.7.152.
• 11. Nakamura Y, Oscherwitz J, Cease KB, et al. Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. Nature. 2013;503(7476):397-401. doi: 10.1038/nature12655.
• 12. Lee SH, Kim KH, Lee SM, et al. STAT3 blockade ameliorates LPS-induced kidney injury through macrophage-driven inflammation. Cell Commun Signal. 2024;22(1):476. doi: 10.1186/s12964-024-01841-1.
• 13. Jeong S, Kang C, Park S, et al. Eletrophilic Chemistry of Tranilast Is Involved in Its Anti-Colitic Activity via Nrf2-HO-1 Pathway Activation. Pharmaceuticals (Basel). 2021;14(11):1092. doi: 10.3390/ph14111092.
• 14. Yin DD, Luo JH, Zhao ZY, Liao YJ, Li Y. Tranilast prevents renal interstitial fibrosis by blocking mast cell infiltration in a rat model of diabetic kidney disease. Mol Med Rep. 2018;17(5):7356-7364. doi: 10.3892/mmr.2018.8776.
• 15. Remick DG. Pathophysiology of sepsis. Am J Pathol. 2007;170(5):1435-1444. doi: 10.2353/ajpath.2007.060872.
• 16. Erbaş O, Taşkıran D. Sepsis-induced changes in behavioral stereotypy in rats; involvement of tumor necrosis factor-alpha, oxidative stress, and dopamine turnover. J Surg Res. 2014;186(1):262-268. doi: 10.1016/j.jss.2013.08.001.
• 17. Tan Z, Liu Q, Chen H, et al. Pectolinarigenin alleviated septic acute kidney injury via inhibiting Jak2/Stat3 signaling and mitochondria dysfunction. Biomed Pharmacother. 2023;159:114286. doi: 10.1016/j.biopha.2023.114286.
• 18. Tan SM, Zhang Y, Cox AJ, Kelly DJ, Qi W. Tranilast attenuates the up-regulation of thioredoxin-interacting protein and oxidative stress in an experimental model of diabetic nephropathy. Nephrol Dial Transplant. 2011;26(1):100-110. doi: 10.1093/ndt/gfq355.
• 19. Başol N, Erbaş O, Çavuşoğlu T, Meral A, Ateş U. Beneficial effects of agomelatine in experimental model of sepsis-related acute kidney injury. Ulus Travma Acil Cerrahi Derg. 2016;22(2):121-126. doi: 10.5505/tjtes.2015.29499.
• 20. Vidyasagar A, Reese S, Acun Z, Hullett D, Djamali A. HSP27 is involved in the pathogenesis of kidney tubulointerstitial fibrosis. Am J Physiol Renal Physiol. 2008;295(3):F707-716. doi: 10.1152/ajprenal.90240.2008.
• 21. Li X, Zhou W, Chen J, et al. Circ_001653 alleviates sepsis associated-acute kidney injury by recruiting BUD13 to regulate KEAP1/NRF2/HO-1 signaling pathway. J Inflamm (Lond). 2024;21(1):37. doi: 10.1186/s12950-024-00409-7.
• 22. Vincent JL, Jones G, David S, Olariu E, Cadwell KK. Frequency and mortality of septic shock in Europe and North America: a systematic review and meta-analysis. Crit Care. 2019;23(1):196. doi: 10.1186/s13054-019-2478-6.
• 23. Qiongyue Z, Xin Y, Meng P, et al. Post-treatment With Irisin Attenuates Acute Kidney Injury in Sepsis Mice Through Anti-Ferroptosis via the SIRT1/Nrf2 Pathway. Front Pharmacol. 2022;13:857067. doi: 10.3389/fphar.2022.857067.
• 24. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-377. doi: 10.1007/s00134-017-4683-6.
• 25. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. doi: 10.1001/jama.2016.0287.
• 26. Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395(10219):200-211. doi: 10.1016/S0140-6736(19)32989-7.
• 27. Hotchkiss RS, Moldawer LL, Opal SM, Reinhart K, Turnbull IR, Vincent JL. Sepsis and septic shock. Nat Rev Dis Primers. 2016;2:16045. doi: 10.1038/nrdp.2016.45.
• 28. Ronco C, Bellomo R, Kellum JA. Acute kidney injury. Lancet. 2019;394(10212):1949-1964. doi: 10.1016/S0140-6736(19)32563-2.
• 29. Uchino S, Kellum JA, Bellomo R, et al; Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294(7):813-818. doi: 10.1001/jama.294.7.813.
• 30. Bagshaw SM, Uchino S, Bellomo R, et al; Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol. 2007;2(3):431-439. doi: 10.2215/CJN.03681106.
• 31. Poston JT, Koyner JL. Sepsis associated acute kidney injury. BMJ. 2019;364:k4891. doi: 10.1136/bmj.k4891.
• 32. Wu W, Lan W, Jiao X, et al. Pyroptosis in sepsis-associated acute kidney injury: mechanisms and therapeutic perspectives. Crit Care. 2025;29(1):168. doi: 10.1186/s13054-025-05329-3.
• 33. Canovai E, Farré R, De Hertogh G, et al. Tranilast Reduces Intestinal Ischemia Reperfusion Injury in Rats Through the Upregulation of Heme-Oxygenase (HO)-1. J Clin Med. 2025;14(9):3254. doi: 10.3390/jcm14093254.
• 34. Huang G, Zhang Y, Zhang Y, Ma Y. Chronic kidney disease and NLRP3 inflammasome: Pathogenesis, development and targeted therapeutic strategies. Biochem Biophys Rep. 2023;33:101417. doi: 10.1016/j.bbrep.2022.101417.