Skip to main content
Top
Published in: International Urology and Nephrology 2/2014

01-02-2014 | Urology - Original Paper

The effects of preoperative immunosuppressive therapy on ischemia and reperfusion (I/R) injury in healthy rats

Authors: Selcuk Kilinc, Sedat Tan, Efsun Hatice Kolatan, Dane Ruscuklu, Esra Satici, Mehmet Kemiksiz, Lutfi Dalkilic, Umut Eren Erdogdu, Cezmi Karaca

Published in: International Urology and Nephrology | Issue 2/2014

Login to get access

Abstract

Purpose

Warm-ischemia-induced injuries might be encountered during renal transplants from cadavers and healthy donors. Toll-like receptors (TLR) in ischemia–reperfusion (I/R) injury are one of the indicators of intracellular injury pathways. The intensity of ischemic injury is directly proportionate to high TLR levels. To minimize the I/R injury, we investigated TLR2 and TLR4 levels on rats, which were pretreated with tacrolimus (FK506) before I/R.

Methods

Eight Wistar albino rats in the study group were administered .01 mg/kg intramuscular tacrolimus. Administration to the study group was performed 24 and 1 h before warm ischemia. Eight rats in the control group were injected with 0.1 c.c. of distilled water. Blood samples were collected from the tail veins of all the rats on the first, second and third days. Expression levels of TLR2 and TLR4 genes were analyzed using the polymerase chain reaction method, to determine any significant difference between the control and study groups on the days when blood was taken.

Results

TLR2 (p = 0.045) and TLR4 (p = 0.022) levels in the study group were found to be statistically, and significantly, lower than those in the control group, on the second day following warm-ischemia- and reperfusion-induced injury.

Conclusions

Administration of immunosuppressive drugs to healthy donor rats led to a statistically significant reduction in the expression levels of TLR2 and TLR4 in the early period. In light of the data obtained by this study, we hypothesize that a preoperative therapy on donors might have a role in preventing I/R injury.
Literature
1.
go back to reference Dhar DK, Nagasue N, Kimoto T, Uchida M, Takemoto Y, Nakamura T (1992) The salutary effect of FK506 in ischemia-reperfusion injury of the canine liver. Transplantation 54(4):583–588PubMedCrossRef Dhar DK, Nagasue N, Kimoto T, Uchida M, Takemoto Y, Nakamura T (1992) The salutary effect of FK506 in ischemia-reperfusion injury of the canine liver. Transplantation 54(4):583–588PubMedCrossRef
2.
go back to reference Kim BS, Lim SW, Li C, Kim JS, Sun BK, Ahn KO, Han SW, Kim J, Yang CW (2005) Ischemia-reperfusion injury activates innate immunity in rat kidneys. Transplantation 79(10):1370–1377PubMedCrossRef Kim BS, Lim SW, Li C, Kim JS, Sun BK, Ahn KO, Han SW, Kim J, Yang CW (2005) Ischemia-reperfusion injury activates innate immunity in rat kidneys. Transplantation 79(10):1370–1377PubMedCrossRef
3.
go back to reference Hayashi S, Ito M, Yasutomi M, Namii Y, Yokoyama I, Uchida K, Takagi H (1995) Evidence that donor pretreatment with FK506 has a synergistic effect on graft prolongation in hamster-to-rat heart xenotransplantation. J Heart Lung Transpl 14(3):579–584 Hayashi S, Ito M, Yasutomi M, Namii Y, Yokoyama I, Uchida K, Takagi H (1995) Evidence that donor pretreatment with FK506 has a synergistic effect on graft prolongation in hamster-to-rat heart xenotransplantation. J Heart Lung Transpl 14(3):579–584
4.
go back to reference Valdivia LA, Monden M, Gotoh M, Hasuike Y, Kubota N, Ichikawa T, Okamura J, Mori T (1987) Prolonged survival of hamster-to-rat liver xenografts using splenectomy and cyclosporine administration. Transplantation 44(6):759–763PubMedCrossRef Valdivia LA, Monden M, Gotoh M, Hasuike Y, Kubota N, Ichikawa T, Okamura J, Mori T (1987) Prolonged survival of hamster-to-rat liver xenografts using splenectomy and cyclosporine administration. Transplantation 44(6):759–763PubMedCrossRef
5.
go back to reference Valdivia LA, Monden M, Gotoh M, Nakano Y, Tono T, Mori T (1990) Evidence that deoxyspergualin prevents sensitization and first-set cardiac xenograft rejection in rats by suppression of antibody formation. Transplantation 50(1):132–136PubMedCrossRef Valdivia LA, Monden M, Gotoh M, Nakano Y, Tono T, Mori T (1990) Evidence that deoxyspergualin prevents sensitization and first-set cardiac xenograft rejection in rats by suppression of antibody formation. Transplantation 50(1):132–136PubMedCrossRef
6.
go back to reference Yamaguchi Y, Halperin EC, Harland RC, Wyble C, Bollinger RR (1990) Significant prolongation of hamster liver transplant survival in Lewis rats by total-lymphoid irradiation, cyclosporine, and splenectomy. Transplantation 49(1):13–17PubMedCrossRef Yamaguchi Y, Halperin EC, Harland RC, Wyble C, Bollinger RR (1990) Significant prolongation of hamster liver transplant survival in Lewis rats by total-lymphoid irradiation, cyclosporine, and splenectomy. Transplantation 49(1):13–17PubMedCrossRef
7.
go back to reference Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2(8):675–680PubMedCrossRef Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2(8):675–680PubMedCrossRef
8.
go back to reference Brightbill HD, Libraty DH, Krutzik SR, Yang RB, Belisle JT, Bleharski JR, Maitland M, Norgard MV, Plevy SE, Smale ST et al (1999) Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285(5428):732–736PubMedCrossRef Brightbill HD, Libraty DH, Krutzik SR, Yang RB, Belisle JT, Bleharski JR, Maitland M, Norgard MV, Plevy SE, Smale ST et al (1999) Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285(5428):732–736PubMedCrossRef
9.
go back to reference Dobrovolskaia MA, Medvedev AE, Thomas KE, Cuesta N, Toshchakov V, Ren T, Cody MJ, Michalek SM, Rice NR, Vogel SN (2003) Induction of in vitro reprogramming by Toll-like receptor (TLR)2 and TLR4 agonists in murine macrophages: effects of TLR “homotolerance” versus “heterotolerance” on NF-kappa B signaling pathway components. J Immunol 170(1):508–519PubMed Dobrovolskaia MA, Medvedev AE, Thomas KE, Cuesta N, Toshchakov V, Ren T, Cody MJ, Michalek SM, Rice NR, Vogel SN (2003) Induction of in vitro reprogramming by Toll-like receptor (TLR)2 and TLR4 agonists in murine macrophages: effects of TLR “homotolerance” versus “heterotolerance” on NF-kappa B signaling pathway components. J Immunol 170(1):508–519PubMed
10.
go back to reference Horng T, Barton GM, Medzhitov R (2001) TIRAP: an adapter molecule in the Toll signaling pathway. Nat Immunol 2(9):835–841PubMedCrossRef Horng T, Barton GM, Medzhitov R (2001) TIRAP: an adapter molecule in the Toll signaling pathway. Nat Immunol 2(9):835–841PubMedCrossRef
11.
go back to reference Silverman N, Maniatis T (2001) NF-kappaB signaling pathways in mammalian and insect innate immunity. Genes Dev 15(18):2321–2342PubMedCrossRef Silverman N, Maniatis T (2001) NF-kappaB signaling pathways in mammalian and insect innate immunity. Genes Dev 15(18):2321–2342PubMedCrossRef
12.
go back to reference Todo S, Fung JJ, Starzl TE, Tzakis A, Demetris AJ, Kormos R, Jain A, Alessiani M, Takaya S, Shapiro R (1990) Liver, kidney, and thoracic organ transplantation under FK 506. Ann Surg 212(3):295–305; discussion 306–297 Todo S, Fung JJ, Starzl TE, Tzakis A, Demetris AJ, Kormos R, Jain A, Alessiani M, Takaya S, Shapiro R (1990) Liver, kidney, and thoracic organ transplantation under FK 506. Ann Surg 212(3):295–305; discussion 306–297
13.
go back to reference Matia I, Varga M, Lodererova A, Adamec M (2010) The positive effect of immunosuppression on adaptation of venous allografts to arterialisation in rats. Eur J Vasc Endovasc Surg 39(4):478–484 Matia I, Varga M, Lodererova A, Adamec M (2010) The positive effect of immunosuppression on adaptation of venous allografts to arterialisation in rats. Eur J Vasc Endovasc Surg 39(4):478–484
14.
go back to reference Varga M, Matia I, Lodererova A, Adamec M (2012) Tacrolimus inhibits intimal hyperplasia in arterialised veins in rats. Bratisl Lek Listy 113(1):5–9 Varga M, Matia I, Lodererova A, Adamec M (2012) Tacrolimus inhibits intimal hyperplasia in arterialised veins in rats. Bratisl Lek Listy 113(1):5–9
15.
go back to reference Zhang FX, Kirschning CJ, Mancinelli R, Xu XP, Jin Y, Faure E, Mantovani A, Rothe M, Muzio M, Arditi M (1999) Bacterial lipopolysaccharide activates nuclear factor-kappaB through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes. J Biol Chem 274(12):7611–7614PubMedCrossRef Zhang FX, Kirschning CJ, Mancinelli R, Xu XP, Jin Y, Faure E, Mantovani A, Rothe M, Muzio M, Arditi M (1999) Bacterial lipopolysaccharide activates nuclear factor-kappaB through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes. J Biol Chem 274(12):7611–7614PubMedCrossRef
16.
go back to reference Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA (1996) The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86(6):973–983PubMedCrossRef Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA (1996) The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86(6):973–983PubMedCrossRef
17.
go back to reference Matsuguchi T, Musikacharoen T, Ogawa T, Yoshikai Y (2000) Gene expressions of Toll-like receptor 2, but not Toll-like receptor 4, is induced by LPS and inflammatory cytokines in mouse macrophages. J Immunol 165(10):5767–5772PubMed Matsuguchi T, Musikacharoen T, Ogawa T, Yoshikai Y (2000) Gene expressions of Toll-like receptor 2, but not Toll-like receptor 4, is induced by LPS and inflammatory cytokines in mouse macrophages. J Immunol 165(10):5767–5772PubMed
18.
go back to reference Medvedev AE, Kopydlowski KM, Vogel SN (2000) Inhibition of lipopolysaccharide-induced signal transduction in endotoxin-tolerized mouse macrophages: dysregulation of cytokine, chemokine, and toll-like receptor 2 and 4 gene expression. J Immunol 164(11):5564–5574PubMed Medvedev AE, Kopydlowski KM, Vogel SN (2000) Inhibition of lipopolysaccharide-induced signal transduction in endotoxin-tolerized mouse macrophages: dysregulation of cytokine, chemokine, and toll-like receptor 2 and 4 gene expression. J Immunol 164(11):5564–5574PubMed
19.
go back to reference Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388(6640):394–397PubMedCrossRef Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388(6640):394–397PubMedCrossRef
20.
go back to reference Yang RB, Mark MR, Gray A, Huang A, Xie MH, Zhang M, Goddard A, Wood WI, Gurney AL, Godowski PJ (1998) Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling. Nature 395(6699):284–288PubMedCrossRef Yang RB, Mark MR, Gray A, Huang A, Xie MH, Zhang M, Goddard A, Wood WI, Gurney AL, Godowski PJ (1998) Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling. Nature 395(6699):284–288PubMedCrossRef
21.
go back to reference Chen L, Wang T, Zhou P, Ma L, Yin D, Shen J, Molinero L, Nozaki T, Phillips T, Uematsu S et al (2006) TLR engagement prevents transplantation tolerance. Am J Transpl 6(10):2282–2291CrossRef Chen L, Wang T, Zhou P, Ma L, Yin D, Shen J, Molinero L, Nozaki T, Phillips T, Uematsu S et al (2006) TLR engagement prevents transplantation tolerance. Am J Transpl 6(10):2282–2291CrossRef
22.
go back to reference Tsung A, Hoffman RA, Izuishi K, Critchlow ND, Nakao A, Chan MH, Lotze MT, Geller DA, Billiar TR (2005) Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells. J Immunol 175(11):7661–7668PubMed Tsung A, Hoffman RA, Izuishi K, Critchlow ND, Nakao A, Chan MH, Lotze MT, Geller DA, Billiar TR (2005) Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells. J Immunol 175(11):7661–7668PubMed
23.
go back to reference Evankovich J (2010) Billiar T. Toll-like receptors in hepatic ischemia/reperfusion and transplantation. Gastroenterol Res Pract, Tsung A Evankovich J (2010) Billiar T. Toll-like receptors in hepatic ischemia/reperfusion and transplantation. Gastroenterol Res Pract, Tsung A
24.
go back to reference Shapiro R, Ellis D, Tan HP, Moritz ML, Basu A, Vats AN, Khan AS, Gray EA, Zeevi A, McFeaters C et al (2006) Antilymphoid antibody preconditioning and tacrolimus monotherapy for pediatric kidney transplantation. J Pediatr 148(6):813–818PubMedCentralPubMedCrossRef Shapiro R, Ellis D, Tan HP, Moritz ML, Basu A, Vats AN, Khan AS, Gray EA, Zeevi A, McFeaters C et al (2006) Antilymphoid antibody preconditioning and tacrolimus monotherapy for pediatric kidney transplantation. J Pediatr 148(6):813–818PubMedCentralPubMedCrossRef
26.
go back to reference Leemans JC, Stokman G, Claessen N, Rouschop KM, Teske GJ, Kirschning CJ, Akira S, van der Poll T, Weening JJ, Florquin S (2005) Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney. J Clin Invest 115(10):2894–2903PubMedCentralPubMedCrossRef Leemans JC, Stokman G, Claessen N, Rouschop KM, Teske GJ, Kirschning CJ, Akira S, van der Poll T, Weening JJ, Florquin S (2005) Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney. J Clin Invest 115(10):2894–2903PubMedCentralPubMedCrossRef
27.
go back to reference Wolfs TG, Buurman WA, van Schadewijk A, de Vries B, Daemen MA, Hiemstra PS, van ‘t Veer C (2002) In vivo expression of Toll-like receptor 2 and 4 by renal epithelial cells: IFN-gamma and TNF-alpha mediated up-regulation during inflammation. J Immunol 168(3):1286–1293PubMed Wolfs TG, Buurman WA, van Schadewijk A, de Vries B, Daemen MA, Hiemstra PS, van ‘t Veer C (2002) In vivo expression of Toll-like receptor 2 and 4 by renal epithelial cells: IFN-gamma and TNF-alpha mediated up-regulation during inflammation. J Immunol 168(3):1286–1293PubMed
28.
go back to reference Wu HS, Zhang JX, Wang L, Tian Y, Wang H, Rotstein O (2004) Toll-like receptor 4 involvement in hepatic ischemia/reperfusion injury in mice. Hepatobiliary Pancreat Dis Int 3(2):250–253PubMed Wu HS, Zhang JX, Wang L, Tian Y, Wang H, Rotstein O (2004) Toll-like receptor 4 involvement in hepatic ischemia/reperfusion injury in mice. Hepatobiliary Pancreat Dis Int 3(2):250–253PubMed
29.
go back to reference Kruger B, Krick S, Dhillon N, Lerner SM, Ames S, Bromberg JS, Lin M, Walsh L, Vella J, Fischereder M et al (2009) Donor Toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation. Proc Natl Acad Sci USA 106(9):3390–3395PubMedCrossRef Kruger B, Krick S, Dhillon N, Lerner SM, Ames S, Bromberg JS, Lin M, Walsh L, Vella J, Fischereder M et al (2009) Donor Toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation. Proc Natl Acad Sci USA 106(9):3390–3395PubMedCrossRef
30.
go back to reference Rusai K, Sollinger D, Baumann M, Wagner B, Strobl M, Schmaderer C, Roos M, Kirschning C, Heemann U, Lutz J (2010) Toll-like receptors 2 and 4 in renal ischemia/reperfusion injury. Pediatr Nephrol 25(5):853–860 Rusai K, Sollinger D, Baumann M, Wagner B, Strobl M, Schmaderer C, Roos M, Kirschning C, Heemann U, Lutz J (2010) Toll-like receptors 2 and 4 in renal ischemia/reperfusion injury. Pediatr Nephrol 25(5):853–860
31.
go back to reference Grosso G, Corona D, Mistretta A, Zerbo D, Sinagra N, Giaquinta A, Cimino S, Ekser B, Giuffrida G, Leonardi A et al (2012) Delayed graft function and long-term outcome in kidney transplantation. Transplant Proc 44(7):1879–1883 Grosso G, Corona D, Mistretta A, Zerbo D, Sinagra N, Giaquinta A, Cimino S, Ekser B, Giuffrida G, Leonardi A et al (2012) Delayed graft function and long-term outcome in kidney transplantation. Transplant Proc 44(7):1879–1883
32.
go back to reference Howard RJ, Pfaff WW, Brunson ME, Scornik JC, Ramos EL, Peterson JC, Fennell RS, Croker BP (1994) Increased incidence of rejection in patients with delayed graft function. Clin Transpl 8(6):527–531 Howard RJ, Pfaff WW, Brunson ME, Scornik JC, Ramos EL, Peterson JC, Fennell RS, Croker BP (1994) Increased incidence of rejection in patients with delayed graft function. Clin Transpl 8(6):527–531
33.
go back to reference Humar A, Johnson EM, Payne WD, Wrenshall L, Sutherland DE, Najarian JS, Gillingham KJ, Matas AJ (1997) Effect of initial slow graft function on renal allograft rejection and survival. Clin Transplant 11(6):623–627PubMed Humar A, Johnson EM, Payne WD, Wrenshall L, Sutherland DE, Najarian JS, Gillingham KJ, Matas AJ (1997) Effect of initial slow graft function on renal allograft rejection and survival. Clin Transplant 11(6):623–627PubMed
34.
go back to reference Jayaram D, Kommareddi M, Sung RS, Luan FL (2012) Delayed graft function requiring more than one-time dialysis treatment is associated with inferior clinical outcomes. Clin Transpl 26(5):E536–E543 Jayaram D, Kommareddi M, Sung RS, Luan FL (2012) Delayed graft function requiring more than one-time dialysis treatment is associated with inferior clinical outcomes. Clin Transpl 26(5):E536–E543
35.
go back to reference Langer RM, Hene R, Vitko S, Christiaans M, Tedesco-Silva H, Jr., Ciechanowski K, Cassuto E, Rostaing L, Vilatoba M, Machein U et al (2012) Everolimus plus early tacrolimus minimization: a phase III, randomized, open-label, multicentre trial in renal transplantation. Transpl Int 25(5):592–602 Langer RM, Hene R, Vitko S, Christiaans M, Tedesco-Silva H, Jr., Ciechanowski K, Cassuto E, Rostaing L, Vilatoba M, Machein U et al (2012) Everolimus plus early tacrolimus minimization: a phase III, randomized, open-label, multicentre trial in renal transplantation. Transpl Int 25(5):592–602
Metadata
Title
The effects of preoperative immunosuppressive therapy on ischemia and reperfusion (I/R) injury in healthy rats
Authors
Selcuk Kilinc
Sedat Tan
Efsun Hatice Kolatan
Dane Ruscuklu
Esra Satici
Mehmet Kemiksiz
Lutfi Dalkilic
Umut Eren Erdogdu
Cezmi Karaca
Publication date
01-02-2014
Publisher
Springer Netherlands
Published in
International Urology and Nephrology / Issue 2/2014
Print ISSN: 0301-1623
Electronic ISSN: 1573-2584
DOI
https://doi.org/10.1007/s11255-013-0548-2

Other articles of this Issue 2/2014

International Urology and Nephrology 2/2014 Go to the issue
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.