Modulation of Histopathological Changes and Inflammatory Markers in the Testes of Hypertensive Male Rats by Fenofibrate Treatment

Section: Research Paper
Issue
Vol. 48 No. 1 (2026): Volume 48 Issue 1
Pages
1-9

Keywords:

Hypertension, Testes, Fenofibrate, Inflammatory Factors, Testosterone

Abstract

Background: Hypertension impairs reproductive organs function, including the testes. As fenofibrate, a major drug used for treating dyslipidemia, improves endothelial function and has anti-inflammatory properties,


Aim: This study investigates the effects of fenofibrate on histopathological and inflammatory marker changes in induced by hypertension in rat’s testis.


Methods: In this study thirty normal male rats, weighing between 120 and 140 grams and aged six to seven weeks, were used. The rats were divided into three groups: The control negative (n=10), rats that received a standard diet and water only. Control positive rats, the hypertensive group (n=10), received an oral Nω-nitro-l-arginine methyl ester (L-NAME) at a dosage of 40 mg/kg/day for 3 weeks. Treatment group (n=10), L-NAME was administered by the rats at a dosage of 40 mg/kg/day followed by Fenofibrate at a daily dose of 30 mg/kg for 4 weeks.


Results: Fenofibrate significantly decreased the proinflammatory markers and the pathological changes in the testes (testicular degeneration, necrosis, vascular congestion, interstitial edema, and hypospe-rmatogenesis) at a P – value < 0.001 compared with the hypertensive group. These changes were significantly increased in hypertensive group compared to the control group (P- value < 0.001). Fenofibrate also showed increased testosterone levels at a P – value < 0.001 compared to the hypertensive group, where testosterone levels were significantly decreased in hypertensive group compared to the control group (P value < 0.001). However, there was no significant effect of fenofibrate or hypertension on body and testicular weight.


Conclusion: Fenofibrate improves histopathological and inflammatory marker changes induced by hypertension in male rats.


 


 


 


 


 


 


 


 


 


 


 


 

References

  1. Mills KT, Stefanescu A, He J. The global epidemiology of hypertension. Nat Rev Nephrol. 2020;16(4):223-237. https://doi.org/10.1038/s41581-019-0244-2
  2. Lin HY, Lee YT, Chan YW. Animal models for the study of primary and secondary hypertension in humans. Biom Rep. 2016;5(6):653-659. https://doi.org/10.3892/br.2016.784
  3. Colli LG, Belardin LB, Echem C, Akamin EH, Antoniassi MP, Adretta RR et al. Systemic arterial hypertension leads to decreased semen quality and alterations in the testicular microcirculation in rats. Sci Rep. 2019;9(1):11047. https://doi.org/10.1038/s41598-019-47157-w
  4. Feihl F, Liaudet L, Waeber B. The macrocirculation and microcirculation of hypertension. Curr Hypertens Rep. 2009;11(3):182-189. https://doi.org/10.1007/s11906-009-0030-0
  5. Navaneethabalakrishnan S, Goodlett BL, Lopez AH, et al. Hypertension and reproductive dysfunction: a possible role of inflammation and inflammation-associated lymphangiogenesis in gonads. Clin Sci. 2020;134(24):3237-3257. https://doi.org/10.1042/CS20201023
  6. Lou IX, Chen J, Ali K. Relationship between hypertension, antihypertensive drugs and sexual dysfunction in men and women: a literature review. Vasc Health Risk Manag. 2023;19:691-705. https://doi.org/10.2147/VHRM.S439334
  7. Levine H, Jørgensen N, Martino-Andrade A. Temporal trends in sperm count: a systematic review and meta-regression analysis of samples collected globally in the 20th and 21st centuries. Hum Reprod. 2023;29(2):157-176. https://doi.org/10.1093/humupd/dmac035
  8. Eisenberg ML, Li S, Behr B. Relationship between semen production and medical comorbidity. Fertil Steril. 2015;103:66-71. https://doi.org/10.1016/j.fertnstert.2014.10.017
  9. Krzemińska J, Wronka M, Młynarska E. Arterial hypertension—oxidative stress and inflammation. Antioxidants. 2022;11(1):172. https://doi.org/10.3390/antiox11010172
  10. Tanase DM, Gosav EM, Radu S. Arterial hypertension and interleukins: potential therapeutic target or future diagnostic marker? J Hypertens. 2019(1):3159283. https://doi.org/10.1155/2019/3159283
  11. Ambrosino P, D’Anna SE, Grassi G. Is it all about endothelial dysfunction? Focusing on the alteration in endothelial integrity as a key determinant of different pathological mechanisms. Biomedicines. 2022;10(11):2757. https://doi.org/10.3390/biomedicines10112757
  12. Xin R, An D, Li Y. Fenofibrate improves vascular endothelial function in diabetic mice. Biomed Pharmacother. 2019;112:108722. DOI: https://doi.org/10.1016/j.biopha.2019.108722
  13. Alqahtani MJ, Negm WA, Saad HM. Fenofibrate and Diosmetin in a rat model of testicular toxicity: New insight on their protective mechanism through PPAR-α/NRF-2/HO-1 signaling pathway. Biomed Pharmacother. 2023;165:115095. https://doi.org/10.1016/j.biopha.2023.115095
  14. Haruhara K, Tsuboi N, Koike K, Fukui A, Miyazaki Y, Kawamura T, et al. Renal histopathological findings in relation to ambulatory blood pressure in chronic kidney disease patients. Hypertens Res. 2015;38:116–22. https://doi.org/10.1038/hr.2014.140
  15. Thanh TN, Van PD, Cong TD, Le Minh T, Vu QHN. Assessment of testis histopathological changes and spermatogenesis in male mice exposed to chronic scrotal heat stress. J Anim Behav Biometeorol. 2020;8:174–80. https://doi.org/10.31893/jabb.20023
  16. Leong XF, Ng CY, Jaarin K. Animal models in cardiovascular research: hypertension and atherosclerosis. Biomed Res Int. 2015;2015:528757. https://doi.org/10.1155/2015/528757
  17. Pechanova O, Vrankova S, Cebova M. Chronic L Name treatment produces hypertension by different mechanisms in peripheral tissues and brain: role of central eNOS. Pathophysiology. 2020;27(1):46–54. https://doi.org/10.3390/pathophysiology27010007
  18. Kosutova M, Pechanova O, Barta A. Different adaptive NO dependent mechanisms in normal and hypertensive conditions. Molecules. 2019;24(9):1682. https://doi.org/10.3390/molecules24091682
  19. Elmarakby AA, Sullivan JC. Sex differences in hypertension: lessons from spontaneously hypertensive rats (SHR). Clin Sci (Lond). 2021;135(15):1791–1804. https://doi.org/10.1042/CS20201017
  20. Navaneethabalakrishnan S, Goodlett BL, Lopez AH. Hypertension and reproductive dysfunction: a possible role of inflammation and inflammation associated lymphangiogenesis in gonads. Clin Sci (Lond). 2020;134(24):3237–3257. DOI: https://doi.org/10.1042/CS20201023
  21. Di Guardo F, Vloeberghs V, Bardhi E. Low testosterone and semen parameters in male partners of infertile couples undergoing IVF with a total sperm count greater than 5 million. J Clin Med. 2020;9(12):3824. https://doi.org/10.3390/jcm9123824
  22. Hegazy AA, Ahmad MM, Aziz JA. Postnatal changes in the structure of rat testis. J Embryol Stem Cell Res. 2019;3(2):1–9. https://doi.org/10.23880/jes-16000123
  23. Eisenberg ML, Li S, Behr B. Relationship between semen production and medical comorbidity. Fertil Steril. 2015;103:66–71. https://doi.org/10.1016/j.fertnstert.2014.10.017
  24. Bednarski TK, Duda MK, Dobrzyn P. Alterations of lipid metabolism in the heart in spontaneously hypertensive rats precedes left ventricular hypertrophy and cardiac dysfunction. Cells. 2022;11(19):3032. https://doi.org/10.3390/cells11193032
  25. Shehzad A, Rabail R, Munir S. Impact of oats on appetite hormones and body weight management: a review. Curr Nutr Rep. 2023;12(1):66–82. https://doi.org/10.1007/s13668-023-00454-3
  26. Li J, Yang X, Zhou X. The role and mechanism of intestinal flora in blood pressure regulation and hypertension development. Antioxid Redox Signal. 2021;34(10):811–30. https://doi.org/10.1089/ars.2020.8104
  27. Ghosh MK, Wahed MI, Khan RI. Pharmacological screening of fenofibrate-loaded solid dispersion in fructose-induced diabetic rat. J Pharm Pharmacol. 2020;72(7):909–15. https://doi.org/10.1111/jphp.13267
  28. Azu OO. Testicular morphology in spontaneously hypertensive rat model: oxidant status and stereological implications. Andrologia. 2015;47(2):123–37. https://doi.org/10.1111/and.12233
  29. Xu N, Wang Q, Jiang S. Fenofibrate improves vascular endothelial function and contractility in diabetic mice. Redox Biol. 2019;20:87–97. https://doi.org/10.1016/j.redox.2018.09.024
  30. Abdel-Aziz AM, Abozaid SM, Yousef RK. Fenofibrate ameliorates testicular damage in rats with streptozotocin-induced type 1 diabetes: role of HO-1 and p38 MAPK. Pharmacol Rep. 2020;72:1645–56. https://doi.org/10.1007/s43440-020-00096-0
  31. Li Y, Xie D, Li L. Comprehensive analysis of metabolic changes in spontaneously hypertensive rats. Clin Exp Hypertens. 2023;45(1):2190529. https://doi.org/10.1080/10641963.2023.2190529
  32. Boarescu PM, Boarescu I, Pop RM. Evaluation of oxidative stress biomarkers, pro-inflammatory cytokines, and histological changes in experimental hypertension, dyslipidemia, and type 1 diabetes mellitus. Int J Mol Sci. 2022;23(3):1438. https://doi.org/10.3390/ijms23031438
  33. Torres-Narváez JC, Pérez-Torres I, Castrejón-Téllez V. The role of the activation of the TRPV1 receptor and of nitric oxide in changes in endothelial and cardiac function and biomarker levels in hypertensive rats. Int J Environ Res Public Health. 2019;16(19):3576. https://doi.org/10.3390/ijerph16193576
  34. Li J, Yang X, Zhou X. The role and mechanism of intestinal flora in blood pressure regulation and hypertension development. Antioxid Redox Signal. 2021;34(10):811–30. https://doi.org/10.1089/ars.2020.8104
  35. Barrows IR, Ramezani A, Raj DS. Inflammation, immunity, and oxidative stress in hypertension—partners in crime? Adv Chronic Kidney Dis. 2019;26(2):122–30. https://doi.org/10.1053/j.ackd.2019.03.001
  36. Ogawa K, Yagi T, Guo T. Pemafibrate, a selective PPARα modulator, and fenofibrate suppress microglial activation through distinct PPARα and SIRT1-dependent pathways. Biochem Biophys Res Commun. 2020;524(2):385–91. https://doi.org/10.1016/j.bbrc.2020.01.118
  37. Bao W, Kong R, Wang N. PPAR-alpha agonist fenofibrate combined with octreotide acetate in the treatment of acute hyperlipidemia pancreatitis. PPAR Res. 2021;2021(1):6629455. https://doi.org/10.1155/2021/6629455
  38. Gallucci GM, Alsuwayt B, Auclair AM. Fenofibrate downregulates NF-κB signaling to inhibit pro-inflammatory cytokine secretion in human THP-1 macrophages and during primary biliary cholangitis. J Inflamm. 2022;45(6):2570–81. https://doi.org/10.1007/s10753-022-01713-1
  39. Wang F, Jiang J, Xia L. Anovel PPARγ ligand, inhibits the production of inflammatory cytokines in murine macrophages by blocking NF-κB and MAPK pathway]. Int J Dev Neurosci. 2018;71:46–51. https://pubmed.ncbi.nlm.nih.gov/30236201/
  40. Losey P, Ladds E, Laprais M. The role of PPAR activation during the systemic response to brain injury. J Neuroinflamm. 2015;12:99. https://doi.org/10.1186/s12974-015-0295-7
  41. Ketchem JM, Bowman EJ, Isales CM. Male sex hormones, aging, and inflammation. Biogerontology. 2023;24(1):1–25. https://doi.org/10.1007/s10522-022-10002-1
  42. Adebayo A, Olamide A, Helen A. Toxicity effects of amlodipine on the testis histology in adult Wistar rats. Am J Med Med Sci. 2012;2:36–40. https://doi.org/10.5923/j.ajmms.20120203.02
  43. Rashid K, Sil PC. Curcumin ameliorates testicular damage in diabetic rats by suppressing cellular stress-mediated mitochondria and endoplasmic reticulum-dependent apoptotic death. Biochim Biophys Acta Mol Basis Dis. 2015;1852:70–82. https://doi.org/10.1016/j.bbadis.2014.10.013
  44. Hassan N, El-Bassossy H, Zakaria M. Heme oxygenase-1 induction protects against hypertension associated with diabetes: effect on exaggerated vascular contractility. Naunyn Schmiedebergs Arch Pharmacol. 2013;386:217–26. https://doi.org/10.1007/s00210-012-0822-3

Authors

Nali Abdulakader Maaruf

Department of Anatomy and Pathology, College of Medicine, Hawler Medical University

Begard Omer Mustafa

Department of Pharmacology, College of Medicine, Hawler Medical University, KRG/Iraq

Faris Muhammed Mahmood

Department of Anatomy and Pathology, College of Medicine, Hawler Medical University, KRG/Iraq

Paiman Jamal Mohamedamin

1Department of Anatomy and Pathology, College of Medicine, Hawler Medical University, KRG/Iraq

Snur M.A. Hassan

3Department of Anatomy and Pathology, College of Veterinary Medicine, University of Sulaimani, KRG/Iraq

Kawa Fareq Dizaye

Department of Pharmacology, College of Medicine, Hawler Medical University, KRG/Iraq

Identifiers

DOI: 10.33899/acmm.v48.i1.51156

Download this PDF file
PDF

Statistics

How to Cite

1.
Modulation of Histopathological Changes and Inflammatory Markers in the Testes of Hypertensive Male Rats by Fenofibrate Treatment. Ann. coll. Med. Mosul [Internet]. 2026 Jun. 29 [cited 2026 Jul. 18];48(1):1-9. Available from: https://mmed.uomosul.edu.iq/index.php/mmed/article/view/51156

How to Cite

1.
Modulation of Histopathological Changes and Inflammatory Markers in the Testes of Hypertensive Male Rats by Fenofibrate Treatment. Ann. coll. Med. Mosul [Internet]. 2026 Jun. 29 [cited 2026 Jul. 18];48(1):1-9. Available from: https://mmed.uomosul.edu.iq/index.php/mmed/article/view/51156