Protective effect of dapagliﬂozin on colistin-induced renal toxicity
1İzmir Katip Çelebi University Atatürk Research and Training Hospital, Emergency Medicine, İzmir, Turkey
2İzmir Katip Çelebi University, Faculty of Medicine, Department of Physiology, Izmir, Turkey
3Van Yüzüncü Yıl University Department of Biochemistry Van, Turkey
4Demiroğlu Bilim University Depatment of Physiology Istanbul, Turkey
DOI: 10.22514/sv.2021.020 Vol.17,Issue 4,July 2021 pp.92-97
Submitted: 24 December 2020 Accepted: 15 January 2021
Published: 08 July 2021
Objectives: Multiple-drug resistance to Gram-negative bacteria has increased signifi-cantly in recent years. Colistin is increasingly used as a last line of defense against these bacteria. However, colistin has been associated with nephrotoxicity in experimental animals. This study explores the protective effect of dapagliflozin in a rodent model of nephrotoxicity.
Material Method: The present study includes a total of 24 male rats, of which 16 were given a single 20 mg/kg dose of colistin (Colimycin 150 mg/mL) intravenously to induce renal toxicity. The remaining eight rats were given no drugs in order to serve as the control, Group A. The 16 rats treated with colistin were then divided into two groups. Rats in Group B received 0.9% NaCl saline solution at a dose of 30 mL/kg/day intraperitoneally (i.p.) and 10 mg/kg/day dapagliflozin (Forziga 10 mg) via oral gavage. Those in Group C received 0.9% NaCl saline solution at an i.p. dose of 30 mL/kg/day. Both saline and dapagliflozin were administered as described over the course of ten days. The animals were euthanized and blood samples were taken by cardiac puncture for further analysis. Their kidneys were removed for histopathological and biochemical examination.
Results: Levels of creatinine, BUN, KIM-1, and MDA were significantly increased in the 16-rat (Groups B and C) treatment group, in comparison to the control group; however, these biomarkers were significantly normalized in Group B, which had received dapagliflozin in addition to saline. The GSH levels of Group C showed significant decline when compared to those of the control group, and were significantly normalized in Group B. Histologically, in Group 2, we observed severe tubular dilatation and tubular epithelial cell injury in comparison to the control group. These severe anatomical changes were decreased in Group B.
Conclusion: Apart from its positive effect on glucose regulation, which is the usual purpose of dapagliflozin, we observed that in colistin-induced nephrotoxicity, it decreases oxidative stress by inhibiting SGLT-2, and has restorative effects in terms of histopathology and biochemistry. These findings offer hope that the use of dapagliflozin may be protective for contrast nephropathy, which causes renal tubule damage through oxidative mechanisms. Future studies will further clarify the mechanistic action of colistin and dapagliflozin, and may support the hypothesis that dapagliflozin can be used as an adjunctive therapy in all nephrotoxic conditions.
Nephrotoxicity; Colistin; Dapagliflozin; Histopathology
Ejder Saylav Bora,Mumin Alper Erdogan,Ayfer Meral,Zeynep Karakaya,Oytun Erbas. Protective effect of dapagliﬂozin on colistin-induced renal toxicity. Signa Vitae. 2021. 17(4);92-97.
 Sorlí L, Luque S, Grau S, Berenguer N, Segura C, Montero MM, et al. Trough colistin plasma level is an independent risk factor for nephrotoxicity: a prospective observational cohort study. BMC Infectious Diseases. 2013; 13: 380.
 Pogue JM, Lee J, Marchaim D, Yee V, Zhao JJ, Chopra T, et al. Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system. Clinical Infectious Diseases. 2011; 53: 879- 884.
 Ghezzi C, Yu AS, Hirayama BA, Kepe V, Liu J, Scafoglio C, et al. Dapagliflozin binds specifically to sodium-glucose cotransporter 2 in the proximal renal tubule. Journal of the American Society of Nephrology. 2017; 28: 802-810.
 Dai C, Li J, Tang S, Li J, Xiao X. Colistin-induced nephrotoxicity in mice involves the mitochondrial, death receptor, and endoplasmic reticulum pathways. Antimicrobial Agents and Chemotherapy. 2014; 58: 4075-4085.
 Han S, Hagan DL, Taylor JR, Xin L, Meng W, Biller SA, et al. Da-pagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes. 2008; 57: 1723-1729.
 Layton AT, Vallon V, Edwards A. Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron. American Journal of Physiology-Renal Physiology. 2016; 310: F1269-F1283.
 Kim JH, Lee SS, Jung MH, Yeo HD, Kim HJ, Yang JI, et al. N- acetylcysteine attenuates glycerol-induced acute kidney injury by regulating MAPKs and Bcl-2 family proteins. Nephrology Dialysis Transplantation. 2010; 25: 1435-1443.
 Demougeot C, Marie C, Beley A. Importance of iron location in iron-induced hydroxyl radical production by brain slices. Life Sciences. 2000; 67: 399-410.
 Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry. 1976; 72: 248-254.
 Ellman GL. Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics. 1959; 82: 70-77.
 Li J, Nation RL, Milne RW, Turnidge JD, Coulthard K. Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria. International Journal of Antimicrobial Agents. 2005; 25: 11-25.
 Ozyilmaz E, Ebinc FA, Derici U, Gulbahar O, Goktas G, Elmas C, et al. Could nephrotoxicity due to colistin be ameliorated with the use of N-acetylcysteine? Intensive Care Medicine. 2010; 37: 141-146.
 Mosenzon O, Wiviott SD, Cahn A, Rozenberg A, Yanuv I, Goodrich EL, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. The Lancet Diabetes & Endocrinology. 2019; 7: 606-617.
 Ichimura T, Hung CC, Yang SA, Stevens JL, Bonventre JV. Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury. American Journal of Physiology-Renal Physiology. 2004; 286: F552-F563.
 Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV. Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney International. 2002; 62: 237-244.
 Cuzzocrea S, Mazzon E, Dugo L, Serraino I, Di Paola R, Britti D, et al. A role for superoxide in gentamicin-mediated nephropathy in rats. European Journal of Pharmacology. 2002; 450: 67-76.
 Lopez-Novoa JM, Quiros Y, Vicente L, Morales AI, Lopez-Hernandez FJ. New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view. Kidney International. 2011; 79: 33-45.
 Walker PD, Barri Y, Shah SV. Oxidant mechanisms in gentamicin nephrotoxicity. Renal Failure. 1999; 21: 433-442.
 Ghlissi Z, Hakim A, Sila A, Mnif H, Zeghal K, Rebai T, et al. Evaluation of efficacy of natural astaxanthin and vitamin E in prevention of colistin-induced nephrotoxicity in the rat model. Environmental Toxicology and Pharmacology. 2014; 37: 960-966.
 Lee TW, Bae E, Kim JH, Jang HN, Cho HS, Chang S, et al. The aqueous extract of aged black garlic ameliorates colistin-induced acute kidney injury in rats. Renal Failure. 2019; 41: 24-33.
 Yousef JM, Chen G, Hill PA, Nation RL, Li J. Ascorbic acid protects against the nephrotoxicity and apoptosis caused by colistin and affects its pharmacokinetics. The Journal of Antimicrobial Chemotherapy. 2012; 67: 452-459.
 Poornima VP, Elizabeth AA. Efficacy of dapagliflozin on oxidative stress-in vitro study. International Journal of Scientific Research. 2019; 8.
 Chen YY, Wu TT, Ho CY, Yeh TC, Sun GC, Kung YH, et al. Dapagliflozin prevents NOX- and SGLT2-dependent oxidative stress in lens cells exposed to fructose-induced diabetes mellitus. International Journal of Molecular Sciences. 2019; 20: 4357.
 Chang YK, Choi H, Jeong JY, Na KR, Lee KW, Lim BJ, et al. Dapagliflozin, SGLT2 inhibitor, attenuates renal ischemia-reperfusion injury. PLoS ONE. 2016;11: e0158810.
 Gilbert RE. SGLT2 inhibitors: β blockers for the kidney? The Lancet Diabetes & Endocrinology. 2016; 4: 814.
 Sano M, Takei M, Shiraishi Y, Suzuki Y. Increased hematocrit during sodium-glucose cotransporter 2 inhibitor therapy indicates recovery of tubulointerstitial function in diabetic kidneys. Journal of Clinical Medicine Research. 2016; 8: 844-847.
 Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. Journal of the American Society of Nephrology. 2006; 17: 17-25.
 O’Neill J, Fasching A, Pihl L, Patinha D, Franzén S, Palm F. Acute SGLT inhibition normalizes O2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats. American Journal of Physiology-Renal Physiology. 2015; 309: F227-F234.
Science Citation Index Expanded (SciSearch) Created as SCI in 1964, Science Citation Index Expanded now indexes over 9,200 of the world’s most impactful journals across 178 scientific disciplines. More than 53 million records and 1.18 billion cited references date back from 1900 to present.
Journal Citation Reports/Science Edition Journal Citation Reports/Science Edition aims to evaluate a journal’s value from multiple perspectives including the journal impact factor, descriptive data about a journal’s open access content as well as contributing authors, and provide readers a transparent and publisher-neutral data & statistics information about the journal.
Chemical Abstracts Service Source Index The CAS Source Index (CASSI) Search Tool is an online resource that can quickly identify or confirm journal titles and abbreviations for publications indexed by CAS since 1907, including serial and non-serial scientific and technical publications.
Index Copernicus The Index Copernicus International (ICI) Journals database’s is an international indexation database of scientific journals. It covered international scientific journals which divided into general information, contents of individual issues, detailed bibliography (references) sections for every publication, as well as full texts of publications in the form of attached files (optional). For now, there are more than 58,000 scientific journals registered at ICI.
Geneva Foundation for Medical Education and Research The Geneva Foundation for Medical Education and Research (GFMER) is a non-profit organization established in 2002 and it works in close collaboration with the World Health Organization (WHO). The overall objectives of the Foundation are to promote and develop health education and research programs.
Scopus: CiteScore 1.0 (2022) Scopus is Elsevier's abstract and citation database launched in 2004. Scopus covers nearly 36,377 titles (22,794 active titles and 13,583 Inactive titles) from approximately 11,678 publishers, of which 34,346 are peer-reviewed journals in top-level subject fields: life sciences, social sciences, physical sciences and health sciences.
Embase Embase (often styled EMBASE for Excerpta Medica dataBASE), produced by Elsevier, is a biomedical and pharmacological database of published literature designed to support information managers and pharmacovigilance in complying with the regulatory requirements of a licensed drug.