Histopathological study of diclofenac induced acute renal failure under lipoic acid and bosentan therapy in male albino rats


  • Lina Bahjat Qasim Pharmacology and Toxicology Department, College of Pharmacy, Mustansiriyah University
  • Ghaith A. Jasim Pharmacology and Toxicology Department, College of Pharmacy, Mustansiriyah University
  • Ihsan S. Rabeea Pharmacology and Toxicology Department, College of Pharmacy, Kufa University




acute kidney injury, diclofenac, lipoic acid, bosentan


Acute kidney injury (AKI), formly known as acute renal failure (ARF), is an abrupt and reversible decrease in kidney function as indicated by the glomerular filtration rate (GFR). Diclofenac-induced AKI is due to toxic effect of it on renal glomeruli, resulting in glomerular lesions.

Furthermore, diclofenac causes autolysis, which increase renal intracellular osmolarity that leads to proximal renal tubular dilatations. Lipoic acid (LA) has antioxidant and anti-inflammatory activities. Bosentan is a competitive endothelin A (ETA) and endothelin B (ETB) receptors antagonist. In this study, the evaluation of effectiveness of lipoic acid and bosentan against diclofenac-induced AKI was done by histopathological examination. The results showed that diclofenac caused histopathological changes include; retracted glomerulus, tubular cast, tubule-interstitial inflammation and tubular necrosis. Lipoic acid or bosentan alone could not reduce the histopathological alterations caused by diclofenac. Meanwhile, the combination therapy was able to reduce the histopathological changes significantly (p>0.05). Therefore, the combination therapy of lipoic acid and bosentan showed promising ameliorative effect against diclofenac-induced AKI


- Saxena A, Meshram SV. Predictors of Mortality in Acute Kidney Injury Patients Admitted to Medicine Intensive Care Unit in a Rural Tertiary Care Hospital. Indian Journal of Critical Care Medicine: Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine [Internet]. 2018 Apr;22(4):231.

- Trevor A, Katzung B, Knuidering-Hall M. Katzung & Trevor’s Pharmacology Examination and Board Review,11th Edition. 11th edition. New York Chicago San Francisco Athens London Madrid Mexico City Milan New Delhi Singapore Sydney Toronto: McGraw-Hill Education / Medical; 2015. 592 p.

- Mustafa HN, Alkan I, Deniz ÖG, Altunkaynak BZ, Annaç E, Kaplan S. A Study on the Toxic Effect of Different Doses of Diclofenac Sodium on the Development of the Kidney in the Postnatal Period. Int J Morphol [Internet]. 2019 Sep;37(3):877–84.

- Alkuraishy HM, Al-Gareeb AI, Hussien NR. Diclofenac induced-acute kidney injury is linked with oxidative stress and pro-inflammatory changes in Sprague Dawley rats. Journal of Contemporary Medical Sciences [Internet]. 2019 Jun 28;5(3).

- R S, S U. Diclofenac-induced biochemical changes in nephrotoxicity among male Albino rats. International Journal of Basic & Clinical Pharmacology [Internet]. 2018 Mar 23;7(4):640–3.

- Gaut JP, Liapis H. Acute kidney injury pathology and pathophysiology: a retrospective review. Clinical Kidney Journal [Internet]. 2021 Feb 1;14(2):526–36.

- Asci H, Saygin M, Cankara FN, Bayram D, Yesilot S, Candan IA, et al. The impact of alpha-lipoic acid on amikacin-induced nephrotoxicity. Renal Failure [Internet]. 2015 Jan 2 [;37(1):117–21.

- Higuchi M. Chapter 15 - Antioxidant Properties of Wheat Bran against Oxidative Stress. In: Watson RR, Preedy VR, Zibadi S, editors. Wheat and Rice in Disease Prevention and Health [Internet]. San Diego: Academic Press; 2014. p. 181–99.

- Ishii HM, Murakashi E, Igarashi-Takeuchi H, Shoji H, Numabe Y. Alpha-Lipoic Acid inhibits NF-κB signal transduced inflammatory cytokines secretion in LPS-induced Human Gingival Fibroblasts. Nihon Shishubyo Gakkai Kaishi (Journal of the Japanese Society of Periodontology). 2017;59(1):28–38.

- PubChem. Bosentan [Internet]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/104865

- Dingemanse J, van Giersbergen P. Clinical Pharmacology of Bosentan, a Dual Endothelin Receptor Antagonist. Clinical pharmacokinetics. 2004 Dec 1; 43:1089–115.

- Lund AK. 6.14 - Oxidants and Endothelial Dysfunction. In: McQueen CA, editor. Comprehensive Toxicology (Second Edition) [Internet]. Oxford: Elsevier; 2010. p. 243–74.

- Sin A, Tang W, Wen CY, Chung SK, Chiu KY. The emerging role of endothelin-1 in the pathogenesis of subchondral bone disturbance and osteoarthritis. Osteoarthritis and Cartilage [Internet]. 2015 Apr 1;23(4):516–24.

- Kowalczyk A, Kleniewska P, Kolodziejczyk M, Skibska B, Goraca A. The Role of Endothelin-1 and Endothelin Receptor Antagonists in Inflammatory Response and Sepsis. Arch Immunol Ther Exp (Warsz) [Internet]. 2015;63(1):41–52.

- Alcalde-Estévez E, Asenjo-Bueno A, Sosa P, Olmos G, Plaza P, Caballero-Mora MÁ, et al. Endothelin-1 induces cellular senescence and fibrosis in cultured myoblasts. A potential mechanism of aging-related sarcopenia. Aging (Albany NY) [Internet]. 2020 Jun 22;12(12):11200–23.

- Paxton S, Peckham M, Knibbs A. The Leeds Histology Guide. 2003

- Khalid U, Pino-Chavez G, Nesargikar P, Jenkins R, Bowen T, Fraser D, et al. Kidney ischaemia reperfusion injury in the rat: The EGTI scoring system as a valid and reliable tool for histological assessment. Journal of Histology and Histopathology. 2016 Jan 1; 3:1.

- Fattori V, Borghi SM, Guazelli CFS, Giroldo AC, Crespigio J, Bussmann AJC, et al. Vinpocetine reduces diclofenac-induced acute kidney injury through inhibition of oxidative stress, apoptosis, cytokine production, and NF-κB activation in mice. Pharmacological Research [Internet]. 2017 Jun 1; 120:10–22.

- Alabi QK, Akomolafe RO. Kolaviron Diminishes Diclofenac-Induced Liver and Kidney Toxicity in Wistar Rats Via Suppressing Inflammatory Events, Upregulating Antioxidant Defenses, and Improving Hematological Indices. Dose Response [Internet]. 2020 Mar 3;18(1):1559325819899256.

- Grdović N, Rajić J, Arambašić Jovanović J, Dinić S, Tolić A, Đorđević M, et al. α-Lipoic Acid Increases Collagen Synthesis and Deposition in Nondiabetic and Diabetic Rat Kidneys. Oxidative Medicine and Cellular Longevity [Internet]. 2021 Mar 12 ;2021: e6669352.

- Çakır T, Polat C, Baştürk A, Gül M, Aslaner A, Durgut H, et al. The effect of alpha lipoic acid on rat kidneys in methotrexate induced oxidative injury. Eur Rev Med Pharmacol Sci. 2015;19(11):2132–9.

- Sharma AK, Kaur J, Kaur T, Singh B, Yadav HN, Pathak D, et al. Ameliorative role of bosentan, an endothelin receptor antagonist, against sodium arsenite–induced renal dysfunction in rats. Environ Sci Pollut Res [Internet]. 2021 Feb ;28(6):7180–90.