Cadmium-induced adrenal cortical autophagy in rats: possible modulation by sildenafil
, 1, 1
Abstract
Background: The link between autophagy, inflammatory bowel disease, ischaemic injury and cancer had been established. Reasonable evidence is available for cadmium to be related to certain cancers. Sildenafil had been investigated to modulate oxidative stress mechanisms. The aim of this study is to investigate cadmium-induced adrenal cortical autophagy and to declare possible modulation by sildenafil.
Materials and methods: Twenty four Wistar rats weighing 150–200 g were randomly and equally assigned into: control group, sildenafil (20 mg/kg/day orally) exposed group, cadmium group (cadmium chloride 1 mg/kg/day SC), cadmium + sildenafil group (rats received cadmium concomitant with sildenafil). Euthanasia was done 4 weeks from the beginning of experiment; adrenal glands were subjected to biochemical, histological, ultrastructural and immunnohistochemical assessment.
Results: Control and sildenafil exposed groups exhibited nearly similar results. Cadmium had produced adrenal cortical apoptosis and ultrastructural derangement of cell organelles. Cadmium-induced autophagy was detected by ultrastructural abundance of enlarged lysosomes and significant (p < 0.05) increase in the optical density of lysosomal associated membrane protein 2 immunoexpression. Sildenafil taken with cadmium had decreased adrenal cortical autophagy, significantly modulated the adrenal gland superoxide dismutase and malondialdehyde compared to cadmium group. Also, the optical density of nuclear factor kappa B (NF-kB) and caspase-3 immunoexpression was significantly decreased in cadmium + sildenafil compared to cadmium group.
Conclusions: Cadmium might induce adrenal cortical autophagy in rats and sildenafil might show an ameliorating effect probably through enhancement of antioxidant defence mechanism and modulation of NF-kB.
Keywords: autophagycadmiumadrenalsildenafil rats
References
- Adeyanju AA, Molehinn OR, Ige ET, et al. Sildenafil, a phosphodiesterase-5-inhibitor decreased the oxidative stress induced by carbon tetrachloride in the rat kidney: A preliminary study. J Applied Pharmaceutical Scien. 2018.
- Aktas C, Kanter M, Erboga M, et al. Anti-apoptotic effects of curcumin on cadmium-induced apoptosis in rat testes. Toxicol Ind Health. 2012; 28(2): 122–130.
- Ansari MN, Aloliet RI, Ganaie MA, et al. Roflumilast, a phosphodiesterase 4 inhibitor, attenuates cadmium-induced renal toxicity via modulation of NF-κB activation and induction of NQO1 in rats. Hum Exp Toxicol. 2019; 38(5): 588–597.
- Bury J. Responses to cellular injury, In: Cross SS, editor. 7th edition. Underwood's Pathology, Elsevier 2019: 77–94.
- Cadirci E, Halici Z, Odabasoglu F, et al. Sildenafil treatment attenuates lung and kidney injury due to overproduction of oxidant activity in a rat model of sepsis: a biochemical and histopathological study. Clin Exp Immunol. 2011; 166(3): 374–384.
- Caretti A, Bianciardi P, Ronchi R, et al. Phosphodiesterase-5 inhibition abolishes neuron apoptosis induced by chronic hypoxia independently of hypoxia-inducible factor-1alpha signaling. Exp Biol Med (Maywood). 2008; 233(10): 1222–1230.
- Das A, Durrant D, Salloum FN, et al. PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer. Pharmacol Ther. 2015; 147: 12–21.
- Das A, Xi L, Kukreja RC. Protein kinase G-dependent cardioprotective mechanism of phosphodiesterase-5 inhibition involves phosphorylation of ERK and GSK3beta. J Biol Chem. 2008; 283(43): 29572–29585.
- Ding G, Jiang Q, Li L, et al. Longitudinal magnetic resonance imaging of sildenafil treatment of embolic stroke in aged rats. Stroke. 2011; 42(12): 3537–3541.
- Djavaheri-Mergny M, Maiuri MC, Kroemer G. Cross talk between apoptosis and autophagy by caspase-mediated cleavage of Beclin 1. Oncogene. 2010; 29(12): 1717–1719.
- Giordano S, Darley-Usmar V, Zhang J. Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease. Redox Biol. 2014; 2: 82–90.
- Khalaf HA, Ghoneim FM, Arafat EA, et al. Histological effect of nicotine on adrenal zona fasciculata and the effect of grape seed extract with or without withdrawal of nicotine. J Microsc Ultrastruct. 2017; 5(3): 123–131.
- Kierszenbaum A, Tres L. Endocrine system. Histology and Cell Biology: An Introduction to Pathology. Chapter 19. Saunders, an imprint of Elsevier Inc, Philadelphia. 2016: 561–581.
- Klionsky DJ, Abdelmohsen K, Abe A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016; 12(1): 1–222.
- Kumar V, Abbas AK, Aster JC. Neoplasia In: Robbins Basic Pathology, 10th edition. Chapter 6. Elsevier, Philadelphia 2018: 189–242.
- Kumar V, Abbas AK, Aster JC. Cell Injury, Cell Death, and Adaptations. In: Robbins Basic Pathology, 10th edition. Chapter 2. Elsevier, Philadelphia 2018: 31–56.
- Li L, Jiang Q, Zhang Li, et al. Angiogenesis and improved cerebral blood flow in the ischemic boundary area detected by MRI after administration of sildenafil to rats with embolic stroke. Brain Res. 2007; 1132(1): 185–192.
- Liang Y, Chen G, Yang Y, et al. Effect of canonical NF-κB signaling pathway on the differentiation of rat dental epithelial stem cells. Stem Cell Res Ther. 2019; 10(1): 139.
- Lowe JS, Anderson PG, Anderson SI. The Cell. In: Stevens & Lowe's Human Histology, 5th edition. Chapter 2. Elsevier, Philadelphia 2020: 12–40.
- Morsy MA, Ibrahim SA, Amin EF, et al. Sildenafil ameliorates gentamicin-induced nephrotoxicity in rats: role of iNOS and eNOS. J Toxicol. 2014; 2014: 489382.
- Mutsuga M, Asaoka Y, Imura N, et al. Aminoglutethimide-induced lysosomal changes in adrenal gland in mice. Exp Toxicol Pathol. 2017; 69(7): 424–429.
- Orororo OC, Asagba SO, Tonukari NJ, et al. Effects of Hibiscus Sabdarrifa L. anthocyanins on cadmium-induced oxidative stress in Wistar rats. J Appl Sci Environ Manag. 2018; 22(4): 465.
- Rapisarda V, Miozzi E, Loreto C, et al. Cadmium exposure and prostate cancer: insights, mechanisms and perspectives. Front Biosci (Landmark Ed). 2018; 23: 1687–1700.
- Rosol TJ, Yarrington JT, Latendresse J, et al. Adrenal gland: structure, function, and mechanisms of toxicity. Toxicol Pathol. 2001; 29(1): 41–48.
- Sanderson S, Wild G, Cull AM, Marston J, Zardin G. Immunohistochemical and immunofluorescent techniques. In: Suvarna SK, Layton C, Bancroft, JD, Editors. Bancroft's Theory and Practice of Histological Techniques, Eighth Edition, Elsevier Limited 2019: 337–394.
- Singh R, Cuervo AM. Lipophagy: connecting autophagy and lipid metabolism. Int J Cell Biol. 2012; 2012: 282041.
- Tulis DA, Middlemas DS. Vasodilators for Hypertensive Crises, Pulmonary Hypertension, and Erectile Dysfunction. In Brody's Human Pharmacology, Wecker L, Taylor DA, Theobald RJ. Elsevier, Kirksville, Missouri. 6th edition 2019: 330–336.
- Williams JA, Ding WX. A mechanistic review of mitophagy and its role in protection against alcoholic liver disease. Biomolecules. 2015; 5(4): 2619–2642.
- Yuan G, Dai S, Yin Z, et al. Sub-chronic lead and cadmium co-induce apoptosis protein expression in liver and kidney of rats. Int J Clin Exp Pathol. 2014; 7: 2905–2914.
- Zhang R, Wang Y, Zhang Li, et al. Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke. 2002; 33(11): 2675–2680.
- Zhu X, Huang Li, Gong J, et al. NF-B pathway link with ER stress-induced autophagy and apoptosis in cervical tumor cells. Cell Death Discov. 2017; 3: 17059.
