Protective Effects of N-Acetylcysteine, Carvedilol, and Paricalcitol in a Rat Model of Peritoneal Fibrosis

Abstract

Aim: This study aimed to evaluate the potential protective effects of paricalcitol, N-acetylcysteine (NAC), and carvedilol in a rat model of chlorhexidine gluconate–induced peritoneal fibrosis.
Material and Methods: Thirty-six female Wistar albino rats were randomized into six groups (n=6 each). Peritoneal fibrosis was induced with daily intraperitoneal chlorhexidine gluconate injections for 21 days. Treatment groups received paricalcitol, NAC, or carvedilol, alone or in combination. Serum TGF-β1 levels and histopathological parameters (peritoneal thickness, fibrosis, inflammation, vascularization) were assessed.
Results: Serum TGF-β1 was significantly higher in the chlorhexidine group compared to controls (58.29 ± 4.40 vs. 49.06 ± 2.35 ng/mL, p<0.05). NAC significantly reduced TGF-β1 compared to chlorhexidine alone (46.76 ± 4.79 ng/mL, p<0.05). Peritoneal thickness was markedly increased in the chlorhexidine group (245 ± 27.3 µm vs. 22.3 ± 2.6 µm in controls, p<0.01) but attenuated by NAC (169.8 ± 30.8 µm, p<0.01) and carvedilol (146.5 ± 43.1 µm, p<0.01). Fibrosis and inflammation scores were also reduced in NAC and carvedilol groups (all p<0.05). Paricalcitol alone showed only partial and non-significant effects.
Conclusions: NAC demonstrated consistent antifibrotic and anti-inflammatory effects, while carvedilol provided moderate benefit and paricalcitol had limited efficacy. These findings suggest that antioxidant therapy, particularly NAC, may represent a potential strategy for preserving peritoneal membrane integrity, though further studies are warranted.

Keywords

• Peritoneal fibrosis
• peritoneal dialysis
• n-acetylcysteine
• carvedilol
• paricalcitol

Supporting Institution

This research received no external funding.

Ethical Statement

Ethical Approval: This study was conducted as a prospective, randomized, and controlled experimental investigation. Ethical approval was obtained from the Gazi University Animal Research Ethics Committee (Project No: 12081, Date: 25 September 2012, Approval Code: 141-18973). All procedures were performed in accordance with the ARRIVE guidelines, and every effort was made to minimize animal suffering throughout the experiment.

Thanks

The authors do not wish to acknowledge any individual or institution.

References

1. 1. Xie K, Cao H, Ling S, Zhong J, Chen H, Chen P, et al. Global, regional, and national burden of chronic kidney disease, 1990-2021: a systematic analysis for the global burden of disease study 2021. Front Endocrinol (Lausanne). 2025;16:1526482. doi:10.3389/fendo.2025.1526482.
2. 2. Abecassis M, Bartlett ST, Collins AJ, Davis CL, Delmonico FL, Friedewald JJ, et al. Kidney transplantation as primary therapy for end-stage renal disease: a National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (NKF/KDOQITM) conference. Clin J Am Soc Nephrol. 2008;3(2):471-80. doi:10.2215/CJN.05021107.
3. 3. Nardelli L, Scalamogna A, Messa P, Gallieni M. Peritoneal dialysis for Potential Kidney Transplant Recipients: pride or Prejudice? Medicina (Kaunas) 2022;58(2):214. doi:10.3390/medicina58020214.
4. 4. Roumeliotis S, Dounousi E, Salmas M, Eleftheriadis T, Liakopoulos V. Unfavorable Effects of Peritoneal Dialysis Solutions on the Peritoneal Membrane: The Role of Oxidative Stress. Biomolecules. 2020;10(5):768. doi:10.3390/biom10050768.
5. 5. Saxena R. Pathogenesis and treatment of peritoneal membrane failure. Pediatr Nephrol. 2008;23(5):695-703. doi:10.1007/s00467-007-0580-5.
6. 6. Terri M, Trionfetti F, Montaldo C, Cordani M, Tripodi M, Lopez-Cabrera M, et al. Mechanisms of Peritoneal Fibrosis: Focus on Immune Cells-Peritoneal Stroma Interactions. Front Immunol. 2021;12:607204. doi:10.3389/fimmu.2021.607204.
7. 7. Moinuddin Z, Summers A, Van Dellen D, Augustine T, Herrick SE. Encapsulating peritoneal sclerosis-a rare but devastating peritoneal disease. Front Physiol. 2014;5:470. doi:10.3389/fphys.2014.00470.
8. 8. Nallagangula KS, Nagaraj SK, Venkataswamy L, Chandrappa M. Liver fibrosis: a compilation on the biomarkers status and their significance during disease progression. Future Sci OA. 2017;4(1):FSO250. doi:10.4155/fsoa-2017-0083.

9. 9. Frangogiannis N. Transforming growth factor-β in tissue fibrosis. J Exp Med. 2020;217(3):e20190103. doi:10.1084/jem.20190103.
10. 10. Tenório MCDS, Graciliano NG, Moura FA, Oliveira ACM, Goulart MOF. N-Acetylcysteine (NAC): impacts on human health. Antioxidants (Basel). 2021;10(6):967. doi:10.3390/antiox10060967.
11. 11. Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther. 2014;141(2):150-9. doi:10.1016/j.pharmthera.2013.09.006.
12. 12. Duplancic D, Cesarik M, Poljak NK, Radman M, Kovacic V, Radic J, et al. The influence of selective vitamin D receptor activator paricalcitol on cardiovascular system and cardiorenal protection. Clin Interv Aging. 2013;8:149-56. doi:10.2147/CIA.S38349.
13. 13. Donate-Correa J, Domínguez-Pimentel V, Muros-de-Fuentes M, Mora-Fernández C, Martín-Núñez E, Cazaña-Pérez V, et al. Beneficial effects of selective vitamin D receptor activation by paricalcitol in chronic kidney disease. Curr Drug Targets. 2014;15(7):703-9. doi:10.2174/1389450115666140417120902.
14. 14. Huo MH, Troiano NW, Pelker RR, Gundberg CM, Friedlaender GE. The influence of ibuprofen on fracture repair: biomechanical, biochemical, histologic, and histomorphometric parameters in rats. J Orthop Res. 1991;9(3):383-90. doi:10.1002/jor.1100090310.
15. 15. Zhang X, Ma Y, You T, Tian X, Zhang H, Zhu Q, et al. Roles of TGF-β/Smad signaling pathway in pathogenesis and development of gluteal muscle contracture. Connect Tissue Res. 2015;56(1):9-17. doi:10.3109/03008207.2014.964400.
16. 16. Evans RA, Tian YC, Steadman R, Phillips AO. TGF-beta1-mediated fibroblast-myofibroblast terminal differentiation-the role of Smad proteins. Exp Cell Res. 2003;282(2):90-100. doi:10.1016/s0014-4827(02)00015-0.
17. 17. Ozaydin M, Peker T, Akcay S, Uysal BA, Yucel H, Icli A, et al. Addition of N-acetyl cysteine to carvedilol decreases the incidence of acute renal injury after cardiac surgery. Clin Cardiol. 2014;37(2):108-14. doi:10.1002/clc.22227.
18. 18. Baba D, Çam K, Şenoğlu Y, Yüksel A, Erdem H, Başaran E. The Efficacy of N-acetylcysteine against renal oxidative stress after extracorporeal shock wave treatment: an experimental rat model. J Urol Surg. 2020;7(1):8-15. doi:10.4274/jus.galenos.2019.2941.
19. 19. Zakaria AY, Badawi R, Osama H, Abdelrahman MA, El-Kalaawy AM. A comparative study of N-Acetyl Cysteine, Rosuvastatin, and Vitamin E in the management of patients with Non-Alcoholic Steatohepatitis: a randomized controlled trial. Pharmaceuticals (Basel). 2025;18(5):650. doi:10.3390/ph18050650.
20. 20. Pereira-Filho G, Ferreira C, Schwengber A, Marroni C, Zettler C, Marroni N. Role of N-acetylcysteine on fibrosis and oxidative stress in cirrhotic rats. Arq Gastroenterol. 2008;45(2):156-62. doi:10.1590/s0004-28032008000200013.
21. 21. Sztolsztener K, Bzdęga W, Hodun K, Chabowski A. N-acetylcysteine decreases myocardial content of inflammatory mediators preventing the development of inflammation state and oxidative stress in rats subjected to a high-fat diet. Int J Inflam. 2023;2023:5480199. doi:10.1155/2023/5480199.
22. 22. Singh M, Kim A, Young A, Nguyen D, Monroe CL, Ding T, et al. The mechanism and inflammatory markers involved in the potential use of N-acetylcysteine in chronic pain management. Life (Basel). 2024;14(11):1361. doi:10.3390/life14111361.
23. 23. Hamdy N, El-Demerdash E. New therapeutic aspect for carvedilol: antifibrotic effects of carvedilol in chronic carbon tetrachloride-induced liver damage. Toxicol Appl Pharmacol. 2012;261(3):292-9. doi:10.1016/j.taap.2012.04.012.
24. 24. Lee OYA, Wong ANN, Ho CY, Tse KW, Chan AZ, Leung GP, et al. Potentials of natural antioxidants in reducing inflammation and oxidative stress in Chronic Kidney Disease. Antioxidants (Basel). 2024;13(6):751. doi:10.3390/antiox13060751.
25. 25. Liakopoulos V, Roumeliotis S, Gorny X, Eleftheriadis T, Mertens PR. Oxidative stress in patients undergoing peritoneal dialysis: a current review of the literature. Oxid Med Cell Longev. 2017;2017:3494867. doi:10.1155/2017/3494867.