Characterization of Diclofenac-induced Renal Damage in Normotensive and Hypertensive Rats: A Comparative Analysis

Abstract

Background Diclofenac is the non-steroidal anti-inflammatory drug (NSAID) mostly prescribed worldwide, but it is highly associated with hypertension and acute kidney injury. Despite that, little information is available about the renal effects of diclofenac in hypertensive individuals, which led us to carry out this comparative study between the renal effects of this NSAID in normotensive (NTR) and spontaneously hypertensive rats (SHR).

Methods Male Wistar NTR and SHR were orally treated with vehicle (V: 10 mL/kg) or diclofenac sodium (D: 100 mg/kg) once a day for 3 days. Urine volume, electrolytes excretion (Na⁺, K⁺, Cl^-, and Ca²⁺), urea, creatinine, pH, and osmolarity were evaluated. Furthermore, blood samples and renal tissue were collected to perform biochemical and histological analysis.

Results Diclofenac increased the renal corpuscle and bowman’s space in the SHR, while no microscopic changes were observed in the renal tissue of NTR. Regarding the urinary parameters, diclofenac reduced urine volume, pH, osmolarity, and all electrolytes excretion, followed by decreased urea and creatinine levels in both lineages. Moreover, it also induced hyponatremia, hypokalemia, and hypocalcemia in SHR, while reduced glutathione-S-transferase activity, lipid hydroperoxides, and nitrite levels in renal tissue.

Conclusions The data presented herein demonstrated that diclofenac induces renal damage and impaired renal function in both NTR and SHR, but those effects are exacerbated in SHR, as seen by the histological changes and electrolytes balance disturbance, therefore, reinforcing that diclofenac may increase the risks of cardiovascular events in hypertensive patients.

Keywords

diclofenac sodium - kidney - renal corpuscle - hypertension - diuresis

Publication History

Received: 02 December 2023

Accepted: 26 February 2024

Article published online:
19 March 2024

• References

• 1 Altman R, Bosch B, Brune K. et al. Advances in NSAID development: Evolution of diclofenac products using pharmaceutical technology. Drugs 2015; 75: 859-877
• 2 Alfaro RA, Davis DD. Diclofenac. In: In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021. PMID: 32491802. Elsevier Inc; 2020: 1-7
• 3 McGettigan P, Henry D. Use of Non-Steroidal Anti-Inflammatory Drugs That Elevate Cardiovascular Risk: An Examination of Sales and Essential Medicines Lists in Low-, Middle-, and High-Income Countries. PLoS Med 2013; 10 DOI: 10.1371/journal.pmed.1001388.
• 4 Ulubay M, Yurt KK, Kaplan AA. et al. The use of diclofenac sodium in urological practice: A structural and neurochemical based review. J Chem Neuroanat 2018; 87: 32-36
• 5 Ungprasert P, Cheungpasitporn W, Crowson CS. et al. Individual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: A systematic review and meta-analysis of observational studies. Eur J Intern Med 2015; 26: 285-291 DOI: 10.1016/j.ejim.2015.03.008.
• 6 Gong J, Zhang Z, Zhang X. et al. Effects and possible mechanisms of alpinia officinarum ethanol extract on indomethacin-induced gastric injury in rats. Pharm Biol 2018; 56: 294-301 DOI: 10.1080/13880209.2018.1450426.
• 7 Elliott WJ. Hypertension Curriculum Review Donald G. Vidt, MD, Section Editor. Drug Interactions and Drugs That Affect Blood Pressure. The Journal of Clinical Hypertension 2006; 8: 731-737 DOI: 10.1111/j.1524-6175.2006.05939.x.
• 8 Bhasin B, Velez JCQ. Evaluation of polyuria: The roles of solute loading and water diuresis. American Journal of Kidney Diseases 2016; 67: 507-511 DOI: 10.1053/j.ajkd.2015.10.021.
• 9 Bolda Mariano LN, Boeing T, Cechinel-Filho V. et al. The acute diuretic effects with low-doses of natural prenylated xanthones in rats. EurJ Pharmacol 2020; 884: 173432 DOI: 10.1016/j.ejphar.2020.173432.
• 10 Costa P, Somensi LB, da Silva RCMVAF. et al. Role of the antioxidant properties in the gastroprotective and gastric healing activity promoted by Brazilian green propolis and the healing efficacy of Artepillin C. Inflammopharmacology 2020; 28: 1009–1025 DOI: 10.1007/s10787-019-00649-7.
• 11 Fonseca da Silva R, de CMV, de A. et al. The pathophysiology of acute gastric ulcer development in normotensive and hypertensive rats: A comparative study. Eur J Pharmacol 2020; 887 DOI: 10.1016/j.ejphar.2020.173469.
• 12 Mendes JB, Campos PP, Rocha MA. et al. Cilostazol and pentoxifylline decrease angiogenesis, inflammation, and fibrosis in sponge-induced intraperitoneal adhesion in mice. Life Sci 2009; 84: 537-543 DOI: 10.1016/j.lfs.2009.01.023.
• 13 Hassid A, Konieczkowski M, Dunn MJ. Prostaglandin synthesis in isolated rat kidney glomeruli (prostacyclin/prostaglandin F2%/prostaglandin E2/prostaglandin D2/thromboxane B2).. 1979
• 14 Okamoto K, Aoki K. Development of a strain of spontaneously hypertensive rats. Jpn Circ J 1963; 27: 282-293 DOI: 10.1253/jcj.27.282.
• 15 Trippodo NC, Frohlich ED. Similarities of genetic (spontaneous) hypertension. Man and rat. Circ Res 1981; 48: 309-319 DOI: 10.1161/01.RES.48.3.309.
• 16 Ofstad J, Iversen BM. Glomerular and tubular damage in normotensive and hypertensive rats. Am J Physiol Renal Physiol 2005; 288 DOI: 10.1152/ajprenal.00226.2004.
• 17 Palmer BF. Metabolic complications associated with use of diuretics. Semin Nephrol 2011; 31: 542-552 DOI: 10.1016/j.semnephrol.2011.09.009.
• 18 Störmer J, Gwinner W, Derlin K. et al. A Single Oral Dose of Diclofenac Causes Transition of Experimental Subclinical Acute Kidney Injury to Chronic Kidney Disease. Biomedicines 2022; 10 DOI: 10.3390/BIOMEDICINES10051198.
• 19 Ku E, Lee BJ, Wei J. et al. Hypertension in CKD: Core Curriculum 2019. American Journal of Kidney Diseases 2019; 74: 120-131 DOI: 10.1053/j.ajkd.2018.12.044.
• 20 Kvam FI, Ofstad J, Iversen BM. Role of nitric oxide in the autoregulation of renal blood flow and glomerular filtration rate in aging spontaneously hypertensive rats. Kidney Blood Press Res 2000; 23: 376-384 DOI: 10.1159/000025986.
• 21 Braun MM, Mahowald M. Electrolytes: Sodium Disorders. FP Essent 2017; 459: 11-20
• 22 Brunkhorst R. Hypokalemia. In: Urology at a Glance. Springer Berlin Heidelberg; 2014: 89-91
• 23 Krstic D, Tomic N, Radosavljevic B. et al. Biochemical Markers of Renal Function. Curr Med Chem 2016; 23: 2018-2040 DOI: 10.2174/0929867323666160115130241.
• 24 de Almeida CLB, Cechinel-Filho V, Boeing T. et al. Prolonged diuretic and saluretic effect of nothofagin isolated from Leandra dasytricha (A. Gray) Cogn. leaves in normotensive and hypertensive rats: Role of antioxidant system and renal protection. Chem Biol Interact 2018; 279 DOI: 10.1016/j.cbi.2017.11.021.
• 25 Mariano LNB, Boeing T, Cechinel Filho V. et al. 1,3,5,6-tetrahydroxyxanthone promotes diuresis, renal protection and antiurolithic properties in normotensive and hypertensive rats. Journal of Pharmacy and Pharmacology 2021; 73 DOI: 10.1093/jpp/rgab026.
• 26 Pedersen J, Coskun M, Soendergaard C. et al. Inflammatory pathways of importance for management of inflammatory bowel disease. World J Gastroenterol 2014; 20: 64-77 DOI: 10.3748/wjg.v20.i1.64.
• 27 Manea A. NADPH oxidase-derived reactive oxygen species: Involvement in vascular physiology and pathology. Cell Tissue Res 2010; 342: 325-339
• 28 Abiola TS, Adebayo OC, Babalola OO. et al. Diclofenac-Induced Kidney Damage in Wistar Rats: Involvement of Antioxidant Mechanism. J Biosci Med (Irvine) 2019; 7: 44-57 DOI: 10.4236/JBM.2019.712005.
• 29 de Almeida CLB, Cechinel-Filho V, Boeing T. et al. Prolonged diuretic and saluretic effect of nothofagin isolated from Leandra dasytricha (A. Gray) Cogn. leaves in normotensive and hypertensive rats: Role of antioxidant system and renal protection. Chem Biol Interact 2018; 279: 227-233 DOI: 10.1016/j.cbi.2017.11.021.
• 30 Wang Y, Evangelista S, Liu Y. et al. Beneficial effects of nebivolol and hydrochlorothiazide combination in spontaneously hypertensive rats. Journal of International Medical Research 2013; 41: 603-617 DOI: 10.1177/0300060513477576.
• 31 Townsend DM, Tew KD, Tapiero H. The importance of glutathione in human disease. Biomedicine and Pharmacotherapy 2003; 57: 145-155
• 32 Iversen BM, Kvam FI, Mørkrid L. et al. Effect of cyclooxygenase inhibition on renal blood flow autoregulation in SHR. Am J Physiol 1992; 263 DOI: 10.1152/AJPRENAL.1992.263.3.F534.