Generic placeholder image

Current Molecular Pharmacology

Editor-in-Chief

ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Research Article

The Effect of Fingolimod on Renal Ischemia/Reperfusion Injury in a Rat Model

Author(s): Yasin Bagheri, Elham Ahmadian, Seyyedeh Mina Hejazian, Maryam Raeesi, Sepideh Zununi Vahed* and Mohammadreza Ardalan*

Volume 17, 2024

Published on: 23 October, 2023

Article ID: e250823220363 Pages: 6

DOI: 10.2174/1874467217666230825113406

Price: $65

Abstract

Background: Ischemia/reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) that induces inflammation and oxidative stress. The main goal of the current study was to assess the impact of fingolimod on kidney IRI in rats.

Methods: For this purpose, 18 male Wistar rats (220–250g) were divided into three groups including (i) Sham, (ii) I/R, and (iii) fingolimod+I/R. The last group was pretreated with a single dose of fingolimod (1mg/kg) (intraperitoneal injection) before induction of the I/R injury. Kidney function, oxidative stress marker (malondialdehyde), and antioxidant markers (catalase, superoxide dismutase, glutathione, glutathione peroxidase, and total antioxidant capacity) were determined in the kidney tissue of the rats. Moreover, kidney samples were taken for histological analysis.

Results: Fingolimod pre-treatment could significantly improve the glutathione peroxidase (p<0.01) and glutathione (p<0.001) activities along with the total antioxidant capacity levels (p<0.001) when compared to the I/R group. Moreover, significant recovery of kidney function and histology was seen in the fingolimod+ I/R group compared to the I/R group (p<0.01).

Conclusion: Fingolimod pretreatment could improve renal function, antioxidant capacity, and histological alterations after I/R injury. Hence, it might protect the kidney against IRI-related kidney damage including AKI and transplantation.

[1]
Yang, T.; Zhang, X.M.; Tarnawski, L.; Peleli, M.; Zhuge, Z.; Terrando, N.; Harris, R.A.; Olofsson, P.S.; Larsson, E.; Persson, A.E.G.; Lundberg, J.O.; Weitzberg, E.; Carlstrom, M. Dietary nitrate attenuates renal ischemia-reperfusion injuries by modulation of immune responses and reduction of oxidative stress. Redox Biol., 2017, 13, 320-330.
[http://dx.doi.org/10.1016/j.redox.2017.06.002] [PMID: 28623824]
[2]
Kelly, K.J.; Williams, W.W., Jr; Colvin, R.B.; Bonventre, J.V. Antibody to intercellular adhesion molecule 1 protects the kidney against ischemic injury. Proc. Natl. Acad. Sci., 1994, 91(2), 812-816.
[http://dx.doi.org/10.1073/pnas.91.2.812] [PMID: 7904759]
[3]
Ysebaert, D.K.; De Greef, K.E.; De Beuf, A.; Van Rompay, A.R.; Vercauteren, S.; Persy, V.P.; De brOE, M.E. T cells as mediators in renal ischemia/reperfusion injury. Kidney Int., 2004, 66(2), 491-496.
[http://dx.doi.org/10.1111/j.1523-1755.2004.761_4.x] [PMID: 15253695]
[4]
Burne, M.J.; Daniels, F.; El Ghandour, A.; Mauiyyedi, S.; Colvin, R.B.; O’Donnell, M.P.; Rabb, H. Identification of the CD4+ T cell as a major pathogenic factor in ischemic acute renal failure. J. Clin. Invest., 2001, 108(9), 1283-1290.
[http://dx.doi.org/10.1172/JCI200112080] [PMID: 11696572]
[5]
Sica, F.; Centonze, D.; Buttari, F. Fingolimod immune effects beyond its sequestration ability. Neurol. Ther., 2019, 8(2), 231-240.
[http://dx.doi.org/10.1007/s40120-019-00162-7] [PMID: 31696392]
[6]
Kimura, T.; Hasegawa, T.; Nakai, H.; Azuma, T.; Usui, N.; Sasaki, T.; Okada, A. FTY720 reduces T-cell recruitment into murine intestinal allograft and prevents activation of graft-infiltrating cells. Transplantation, 2003, 75(9), 1469-1474.
[http://dx.doi.org/10.1097/01.TP.0000058816.13525.92] [PMID: 12792499]
[7]
Hwang, M.W.; Matsumori, A.; Furukawa, Y.; Ono, K.; Okada, M.; Iwasaki, A.; Hara, M.; Sasayama, S. FTY720, a new immunosuppressant, promotes long-term graft survival and inhibits the progression of graft coronary artery disease in a murine model of cardiac transplantation. Circulation, 1999, 100(12), 1322-1329.
[http://dx.doi.org/10.1161/01.CIR.100.12.1322] [PMID: 10491378]
[8]
Segoloni, G.P.; Quaglia, M. New immunosuppressive drugs for prevention and treatment of rejection in renal transplant. J. Nephrol., 2006, 19(5), 578-586.
[PMID: 17136684]
[9]
Zwacka, R.M.; Zhang, Y.; Halldorson, J.; Schlossberg, H.; Dudus, L.; Engelhardt, J.F. CD4(+) T-lymphocytes mediate ischemia/reperfusion-induced inflammatory responses in mouse liver. J. Clin. Invest., 1997, 100(2), 279-289.
[http://dx.doi.org/10.1172/JCI119533] [PMID: 9218504]
[10]
Hla, T.; Lee, M.J.; Ancellin, N.; Paik, J.H.; Kluk, M.J. Lysophospholipids--receptor revelations. Science, 2001, 294(5548), 1875-1878.
[http://dx.doi.org/10.1126/science.1065323] [PMID: 11729304]
[11]
Spiegel, S.; Milstien, S. Sphingosine-1-phosphate: An enigmatic signalling lipid. Nat. Rev. Mol. Cell Biol., 2003, 4(5), 397-407.
[http://dx.doi.org/10.1038/nrm1103] [PMID: 12728273]
[12]
Brinkmann, V.; Lynch, K.R. FTY720: targeting G-protein-coupled receptors for sphingosine 1-phosphate in transplantation and autoimmunity. Curr. Opin. Immunol., 2002, 14(5), 569-575.
[http://dx.doi.org/10.1016/S0952-7915(02)00374-6] [PMID: 12183155]
[13]
Mandala, S.; Hajdu, R.; Bergstrom, J.; Quackenbush, E.; Xie, J.; Milligan, J.; Thornton, R.; Shei, G.J.; Card, D.; Keohane, C.; Rosenbach, M.; Hale, J.; Lynch, C.L.; Rupprecht, K.; Parsons, W.; Rosen, H. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science, 2002, 296(5566), 346-349.
[http://dx.doi.org/10.1126/science.1070238] [PMID: 11923495]
[14]
Shaw, B.; Doolen, S.; Iannitti, T.; Donahue, R.; Taylor, B. (184) Fingolimod behaves as an agonist at sphingosine-1-phosphate receptor 1 to inhibit pain in an experimental autoimmune encephalomyelitis model of multiple sclerosis. J. Pain, 2017, 18(4), S22.
[http://dx.doi.org/10.1016/j.jpain.2017.02.091]
[15]
Qian, Y.; Gao, C.; Zhao, X.; Song, Y.; Luo, H.; An, S.; Huang, J.; Zhang, J.; Jiang, R. Fingolimod attenuates lung injury and cardiac dysfunction after traumatic brain injury. J. Neurotrauma, 2020, 37(19), 2131-2140.
[http://dx.doi.org/10.1089/neu.2019.6951] [PMID: 32434456]
[16]
Liu, G.; Bi, Y.; Wang, R.; Yang, H.; Zhang, Y.; Wang, X.; Liu, H.; Lu, Y.; Zhang, Z.; Chen, W.; Chu, Y.; Yang, R. Targeting S1P1 receptor protects against murine immunological hepatic injury through myeloid-derived suppressor cells. J. Immunol., 2014, 192(7), 3068-3079.
[http://dx.doi.org/10.4049/jimmunol.1301193] [PMID: 24567529]
[17]
Rungatscher, A.; Linardi, D.; Naseer, A.; Mani, R.; Hoxha, S.; Luciani, G.B.; Faggian, G. Sphingosine-1-phosphate receptor agonist fingolimod reduces myocardial ischemia-reperfusion injury and apoptosis increasing long-term left ventricular function after heart transplantation. J. Heart Lung Transplant., 2019, 38(4), S223.
[http://dx.doi.org/10.1016/j.healun.2019.01.546]
[18]
Zhang, L.; Sui, R.; Zhang, L. Fingolimod protects against cerebral ischemia reperfusion injury in rats by reducing inflammatory cytokines and inhibiting the activation of p38 MAPK and NF-κB signaling pathways. Neurosci. Lett., 2022, 771, 136413.
[http://dx.doi.org/10.1016/j.neulet.2021.136413] [PMID: 34942319]
[19]
Troncoso, P.; Ortíz, M.; Martínez, L.; Kahan, B.D. FTY 720 prevents ischemic reperfusion damage in rat kidneys. Transplant. Proc., 2001, 33(1-2), 857-859.
[http://dx.doi.org/10.1016/S0041-1345(00)02349-6] [PMID: 11267102]
[20]
Shi, Z.; Li, T.; Kang, D.; Su, H.; Tu, F. Fingolimod attenuates renal ischemia/reperfusion-induced acute lung injury by inhibiting inflammation and apoptosis and modulating S1P metabolism. J. Int. Med. Res., 2021, 49(8)
[http://dx.doi.org/10.1177/03000605211032806] [PMID: 34340580]
[21]
Melnikov, V.Y.; Faubel, S.; Siegmund, B.; Lucia, M.S.; Ljubanovic, D.; Edelstein, C.L. Neutrophil-independent mechanisms of caspase-1– and IL-18–mediated ischemic acute tubular necrosis in mice. J. Clin. Invest., 2002, 110(8), 1083-1091.
[http://dx.doi.org/10.1172/JCI0215623] [PMID: 12393844]
[22]
Man, K.; Ng, K.T.; Lee, T.K.; Chung, M.L.; Sun, C.K.; Xian, L.L.; Zhao, Y.; Ho, J.W.; Sheung, T.F. FTY720 attenuates hepatic ischemia-reperfusion injury in normal and cirrhotic livers. Am. J. Transplant., 2005, 5(1), 40-49.
[http://dx.doi.org/10.1111/j.1600-6143.2004.00642.x] [PMID: 15636610]
[23]
Budde, K.; Schütz, M.; Glander, P.; Peters, H.; Waiser, J.; Liefeldt, L.; Neumayer, H.H.; Böhler, T. FTY720 (fingolimod) in renal transplantation. Clin. Transplant., 2006, 20(s17)(Suppl. 17), 17-24.
[http://dx.doi.org/10.1111/j.1399-0012.2006.00596.x] [PMID: 17100697]
[24]
Müller, H.; Hofer, S.; Kaneider, N.; Neuwirt, H.; Mosheimer, B.; Mayer, G.; Konwalinka, G.; Heufler, C.; Tiefenthaler, M. The immunomodulator FTY720 interferes with effector functions of human monocyte-derived dendritic cells. Eur. J. Immunol., 2005, 35(2), 533-545.
[http://dx.doi.org/10.1002/eji.200425556] [PMID: 15657952]
[25]
Yevgi, R.; Demir, R. Oxidative stress activity of fingolimod in multiple sclerosis. Clin. Neurol. Neurosurg., 2021, 202, 106500.
[http://dx.doi.org/10.1016/j.clineuro.2021.106500] [PMID: 33508648]
[26]
Morales-Ruiz, M.; Lee, M.J.; Zöllner, S.; Gratton, J.P.; Scotland, R.; Shiojima, I.; Walsh, K.; Hla, T.; Sessa, W.C. Sphingosine 1-phosphate activates Akt, nitric oxide production, and chemotaxis through a Gi protein/phosphoinositide 3-kinase pathway in endothelial cells. J. Biol. Chem., 2001, 276(22), 19672-19677.
[http://dx.doi.org/10.1074/jbc.M009993200] [PMID: 11278592]
[27]
Ferrero, M.E. In Vivo vascular leakage assay. In: Tumor Necrosis Factor: Methods and Protocols; Corti, A.; Ghezzi, P., Eds.; Humana Press: Totowa, NJ, 2004; pp. 191-198.
[http://dx.doi.org/10.1385/1-59259-771-8:191]
[28]
Awad, A.S.; Ye, H.; Huang, L.; Li, L.; Foss, F.W., Jr; Macdonald, T.L.; Lynch, K.R.; Okusa, M.D. Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney. Am. J. Physiol. Renal Physiol., 2006, 290(6), F1516-F1524.
[http://dx.doi.org/10.1152/ajprenal.00311.2005] [PMID: 16403835]
[29]
Thangada, S.; Shapiro, L.H.; Silva, C.; Yamase, H.; Hla, T.; Ferrer, F.A. Treatment with the immunomodulator FTY720 (fingolimod) significantly reduces renal inflammation in murine unilateral ureteral obstruction. J. Urol., 2014, 191(5S), 1508-1516.
[http://dx.doi.org/10.1016/j.juro.2013.10.072] [PMID: 24679864]
[30]
Huang, Q.; Liang, Q.; Chen, H.; Wang, M.; Huang, Q.; Zheng, D.; Lin, P. Protective effect of fingolimod on renal ischemia reperfusion injury model mice and its mechanism study. J China Pharmacy, 2018, (12), 54-57.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy