Skip to main content
Top
Published in: Journal of Translational Medicine 1/2014

Open Access 01-12-2014 | Research

Rapamycin protects kidney against ischemia reperfusion injury through recruitment of NKT cells

Authors: Chao Zhang, Long Zheng, Long Li, Lingyan Wang, Liping Li, Shang Huang, Chenli Gu, Lexi Zhang, Cheng Yang, Tongyu Zhu, Ruiming Rong

Published in: Journal of Translational Medicine | Issue 1/2014

Login to get access

Abstract

Background

NKT cells play a protective role in ischemia reperfusion (IR) injury, of which the trafficking in the body and recruitment in injured organs can be influenced by immunosuppressive therapy. Therefore, we investigated the effects of rapamycin on kidneys exposed to IR injury in early stage and on trafficking of NKT cells in a murine model.

Material and methods

Balb/c mice were subjected to kidney 30 min ischemia followed by 24 h reperfusion. Rapamycin (2.5 ml/kg) was administered by gavage daily, starting 1 day before the operation. Renal function and histological changes were assessed. The proportion of NKT cells in peripheral blood, spleen and kidney was detected by flow cytometry. The chemokines and corresponding receptor involved in NKT cell trafficking were determined by RT-PCR and flow cytometry respectively.

Results

Rapamycin significantly improved renal function and ameliorated histological injury. In rapamycin-treated group, the proportion of NKT cells in spleen was significantly decreased but increased in peripheral blood and kidney. In addition, the CXCR3+ NKT cell in the kidney increased remarkably in the rapamycin-treated group. The chemokines, CXCL9 and CXCL10, as the ligands of CXCR3, were also increased in the rapamycin-treated kidney.

Conclusions

Rapamycin may recruit NKT cells from spleen to the IR-induced kidney to ameliorate renal IR injury in the early stage.
Appendix
Available only for authorised users
Literature
1.
go back to reference Perico N, Cattaneo D, Sayegh MH, Remuzzi G: Delayed graft function in kidney transplantation. Lancet. 2004, 364: 1814-1827. 10.1016/S0140-6736(04)17406-0.CrossRefPubMed Perico N, Cattaneo D, Sayegh MH, Remuzzi G: Delayed graft function in kidney transplantation. Lancet. 2004, 364: 1814-1827. 10.1016/S0140-6736(04)17406-0.CrossRefPubMed
2.
go back to reference Goncalves GM, Cenedeze MA, Feitoza CQ, de Paula CB, Marques GD, Pinheiro HS, dos Paula Antunes Teixeira V, Antonia dos Reis M, Pacheco-Silva A, Camara NO: The role of immunosuppressive drugs in aggravating renal ischemia and reperfusion injury. Transplant Proc. 2007, 39: 417-420. 10.1016/j.transproceed.2007.01.027.CrossRefPubMed Goncalves GM, Cenedeze MA, Feitoza CQ, de Paula CB, Marques GD, Pinheiro HS, dos Paula Antunes Teixeira V, Antonia dos Reis M, Pacheco-Silva A, Camara NO: The role of immunosuppressive drugs in aggravating renal ischemia and reperfusion injury. Transplant Proc. 2007, 39: 417-420. 10.1016/j.transproceed.2007.01.027.CrossRefPubMed
3.
go back to reference Kezic A, Becker JU, Thaiss F: The effect of mTOR-inhibition on NF-kappaB activity in kidney ischemia-reperfusion injury in mice. Transplant Proc. 2013, 45: 1708-1714. 10.1016/j.transproceed.2013.02.110.CrossRefPubMed Kezic A, Becker JU, Thaiss F: The effect of mTOR-inhibition on NF-kappaB activity in kidney ischemia-reperfusion injury in mice. Transplant Proc. 2013, 45: 1708-1714. 10.1016/j.transproceed.2013.02.110.CrossRefPubMed
4.
go back to reference Goncalves GM, Cenedeze MA, Feitoza CQ, Wang PM, Bertocchi AP, Damiao MJ, Pinheiro HS, Antunes Teixeira VP, dos Reis MA, Pacheco-Silva A, Camara NO: The role of heme oxygenase 1 in rapamycin-induced renal dysfunction after ischemia and reperfusion injury. Kidney Int. 2006, 70: 1742-1749. 10.1038/sj.ki.5001893.CrossRefPubMed Goncalves GM, Cenedeze MA, Feitoza CQ, Wang PM, Bertocchi AP, Damiao MJ, Pinheiro HS, Antunes Teixeira VP, dos Reis MA, Pacheco-Silva A, Camara NO: The role of heme oxygenase 1 in rapamycin-induced renal dysfunction after ischemia and reperfusion injury. Kidney Int. 2006, 70: 1742-1749. 10.1038/sj.ki.5001893.CrossRefPubMed
5.
go back to reference Kezic A, Thaiss F, Becker JU, Tsui TY, Bajcetic M: Effects of everolimus on oxidative stress in kidney model of ischemia/reperfusion injury. Am J Nephrol. 2013, 37: 291-301. 10.1159/000348496.CrossRefPubMed Kezic A, Thaiss F, Becker JU, Tsui TY, Bajcetic M: Effects of everolimus on oxidative stress in kidney model of ischemia/reperfusion injury. Am J Nephrol. 2013, 37: 291-301. 10.1159/000348496.CrossRefPubMed
6.
go back to reference Vogelbacher R, Wittmann S, Braun A, Daniel C, Hugo C: The mTOR inhibitor everolimus induces proteinuria and renal deterioration in the remnant kidney model in the rat. Transplantation. 2007, 84: 1492-1499. 10.1097/01.tp.0000282866.92367.99.CrossRefPubMed Vogelbacher R, Wittmann S, Braun A, Daniel C, Hugo C: The mTOR inhibitor everolimus induces proteinuria and renal deterioration in the remnant kidney model in the rat. Transplantation. 2007, 84: 1492-1499. 10.1097/01.tp.0000282866.92367.99.CrossRefPubMed
7.
go back to reference Castedo M, Ferri KF, Blanco J, Roumier T, Larochette N, Barretina J, Amendola A, Nardacci R, Metivier D, Este JA, Piacentini M, Kroemer G: Human immunodeficiency virus 1 envelope glycoprotein complex-induced apoptosis involves mammalian target of rapamycin/FKBP12-rapamycin-associated protein-mediated p53 phosphorylation. J Exp Med. 2001, 194: 1097-1110. 10.1084/jem.194.8.1097.PubMedCentralCrossRefPubMed Castedo M, Ferri KF, Blanco J, Roumier T, Larochette N, Barretina J, Amendola A, Nardacci R, Metivier D, Este JA, Piacentini M, Kroemer G: Human immunodeficiency virus 1 envelope glycoprotein complex-induced apoptosis involves mammalian target of rapamycin/FKBP12-rapamycin-associated protein-mediated p53 phosphorylation. J Exp Med. 2001, 194: 1097-1110. 10.1084/jem.194.8.1097.PubMedCentralCrossRefPubMed
8.
go back to reference Weichhart T, Saemann MD: The multiple facets of mTOR in immunity. Trends Immunol. 2009, 30: 218-226. 10.1016/j.it.2009.02.002.CrossRefPubMed Weichhart T, Saemann MD: The multiple facets of mTOR in immunity. Trends Immunol. 2009, 30: 218-226. 10.1016/j.it.2009.02.002.CrossRefPubMed
9.
go back to reference Arrenberg P, Halder R, Kumar V: Cross-regulation between distinct natural killer T cell subsets influences immune response to self and foreign antigens. J Cell Physiol. 2009, 218: 246-250. 10.1002/jcp.21597.PubMedCentralCrossRefPubMed Arrenberg P, Halder R, Kumar V: Cross-regulation between distinct natural killer T cell subsets influences immune response to self and foreign antigens. J Cell Physiol. 2009, 218: 246-250. 10.1002/jcp.21597.PubMedCentralCrossRefPubMed
10.
go back to reference Johnston B, Kim CH, Soler D, Emoto M, Butcher EC: Differential chemokine responses and homing patterns of murine TCR alpha beta NKT cell subsets. J Immunol. 2003, 171: 2960-2969. 10.4049/jimmunol.171.6.2960.CrossRefPubMed Johnston B, Kim CH, Soler D, Emoto M, Butcher EC: Differential chemokine responses and homing patterns of murine TCR alpha beta NKT cell subsets. J Immunol. 2003, 171: 2960-2969. 10.4049/jimmunol.171.6.2960.CrossRefPubMed
11.
go back to reference Yang SH, Jin JZ, Lee SH, Park H, Kim CH, Lee DS, Kim S, Chung NH, Kim YS: Role of NKT cells in allogeneic islet graft survival. Clin Immunol. 2007, 124: 258-266. 10.1016/j.clim.2007.06.003.CrossRefPubMed Yang SH, Jin JZ, Lee SH, Park H, Kim CH, Lee DS, Kim S, Chung NH, Kim YS: Role of NKT cells in allogeneic islet graft survival. Clin Immunol. 2007, 124: 258-266. 10.1016/j.clim.2007.06.003.CrossRefPubMed
12.
go back to reference Oh K, Kim S, Park SH, Gu H, Roopenian D, Chung DH, Kim YS, Lee DS: Direct regulatory role of NKT cells in allogeneic graft survival is dependent on the quantitative strength of antigenicity. J Immunol. 2005, 174: 2030-2036. 10.4049/jimmunol.174.4.2030.CrossRefPubMed Oh K, Kim S, Park SH, Gu H, Roopenian D, Chung DH, Kim YS, Lee DS: Direct regulatory role of NKT cells in allogeneic graft survival is dependent on the quantitative strength of antigenicity. J Immunol. 2005, 174: 2030-2036. 10.4049/jimmunol.174.4.2030.CrossRefPubMed
13.
go back to reference Yang SH, Lee JP, Jang HR, Cha RH, Han SS, Jeon US, Kim DK, Song J, Lee DS, Kim YS: Sulfatide-reactive natural killer T cells abrogate ischemia-reperfusion injury. J Am Soc Nephrol. 2011, 22: 1305-1314. 10.1681/ASN.2010080815.PubMedCentralCrossRefPubMed Yang SH, Lee JP, Jang HR, Cha RH, Han SS, Jeon US, Kim DK, Song J, Lee DS, Kim YS: Sulfatide-reactive natural killer T cells abrogate ischemia-reperfusion injury. J Am Soc Nephrol. 2011, 22: 1305-1314. 10.1681/ASN.2010080815.PubMedCentralCrossRefPubMed
14.
go back to reference Yang C, Zhao T, Lin M, Zhao Z, Hu L, Jia Y, Xue Y, Xu M, Tang Q, Yang B, Rong R, Zhu T: Helix B surface peptide administered after insult of ischemia reperfusion improved renal function, structure and apoptosis through beta common receptor/erythropoietin receptor and PI3K/Akt pathway in a murine model. Exp Biol Med (Maywood). 2013, 238: 111-119. 10.1258/ebm.2012.012185.CrossRef Yang C, Zhao T, Lin M, Zhao Z, Hu L, Jia Y, Xue Y, Xu M, Tang Q, Yang B, Rong R, Zhu T: Helix B surface peptide administered after insult of ischemia reperfusion improved renal function, structure and apoptosis through beta common receptor/erythropoietin receptor and PI3K/Akt pathway in a murine model. Exp Biol Med (Maywood). 2013, 238: 111-119. 10.1258/ebm.2012.012185.CrossRef
15.
go back to reference Kelly KJ, Williams WW, Colvin RB, Meehan SM, Springer TA, Gutierrez-Ramos JC, Bonventre JV: Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury. J Clin Invest. 1996, 97: 1056-1063. 10.1172/JCI118498.PubMedCentralCrossRefPubMed Kelly KJ, Williams WW, Colvin RB, Meehan SM, Springer TA, Gutierrez-Ramos JC, Bonventre JV: Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury. J Clin Invest. 1996, 97: 1056-1063. 10.1172/JCI118498.PubMedCentralCrossRefPubMed
16.
go back to reference Yang C, Li L, Xue Y, Zhao Z, Zhao T, Jia Y, Rong R, Xu M, Nicholson ML, Zhu T, Yang B: Innate immunity activation involved in unprotected porcine auto-transplant kidneys preserved by naked caspase-3 siRNA. J Transl Med. 2013, 11: 210-10.1186/1479-5876-11-210.PubMedCentralCrossRefPubMed Yang C, Li L, Xue Y, Zhao Z, Zhao T, Jia Y, Rong R, Xu M, Nicholson ML, Zhu T, Yang B: Innate immunity activation involved in unprotected porcine auto-transplant kidneys preserved by naked caspase-3 siRNA. J Transl Med. 2013, 11: 210-10.1186/1479-5876-11-210.PubMedCentralCrossRefPubMed
17.
go back to reference Zhao Z, Yang C, Li L, Zhao T, Wang L, Rong R, Yang B, Xu M, Zhu T: Increased peripheral and local soluble FGL2 in the recovery of renal ischemia reperfusion injury in a porcine kidney auto-transplantation model. J Transl Med. 2014, 12: 53-10.1186/1479-5876-12-53.PubMedCentralCrossRefPubMed Zhao Z, Yang C, Li L, Zhao T, Wang L, Rong R, Yang B, Xu M, Zhu T: Increased peripheral and local soluble FGL2 in the recovery of renal ischemia reperfusion injury in a porcine kidney auto-transplantation model. J Transl Med. 2014, 12: 53-10.1186/1479-5876-12-53.PubMedCentralCrossRefPubMed
18.
go back to reference Taniguchi M, Seino K, Nakayama T: The NKT cell system: bridging innate and acquired immunity. Nat Immunol. 2003, 4: 1164-1165. 10.1038/ni1203-1164.CrossRefPubMed Taniguchi M, Seino K, Nakayama T: The NKT cell system: bridging innate and acquired immunity. Nat Immunol. 2003, 4: 1164-1165. 10.1038/ni1203-1164.CrossRefPubMed
19.
go back to reference Cao Z, Yuan Y, Jeyabalan G, Du Q, Tsung A, Geller DA, Billiar TR: Preactivation of NKT cells with alpha-GalCer protects against hepatic ischemia-reperfusion injury in mouse by a mechanism involving IL-13 and adenosine A2A receptor. Am J Physiol Gastrointest Liver Physiol. 2009, 297: G249-G258. 10.1152/ajpgi.00041.2009.PubMedCentralCrossRefPubMed Cao Z, Yuan Y, Jeyabalan G, Du Q, Tsung A, Geller DA, Billiar TR: Preactivation of NKT cells with alpha-GalCer protects against hepatic ischemia-reperfusion injury in mouse by a mechanism involving IL-13 and adenosine A2A receptor. Am J Physiol Gastrointest Liver Physiol. 2009, 297: G249-G258. 10.1152/ajpgi.00041.2009.PubMedCentralCrossRefPubMed
20.
go back to reference Li L, Huang L, Sung SS, Lobo PI, Brown MG, Gregg RK, Engelhard VH, Okusa MD: NKT cell activation mediates neutrophil IFN-gamma production and renal ischemia-reperfusion injury. J Immunol. 2007, 178: 5899-5911. 10.4049/jimmunol.178.9.5899.CrossRefPubMed Li L, Huang L, Sung SS, Lobo PI, Brown MG, Gregg RK, Engelhard VH, Okusa MD: NKT cell activation mediates neutrophil IFN-gamma production and renal ischemia-reperfusion injury. J Immunol. 2007, 178: 5899-5911. 10.4049/jimmunol.178.9.5899.CrossRefPubMed
Metadata
Title
Rapamycin protects kidney against ischemia reperfusion injury through recruitment of NKT cells
Authors
Chao Zhang
Long Zheng
Long Li
Lingyan Wang
Liping Li
Shang Huang
Chenli Gu
Lexi Zhang
Cheng Yang
Tongyu Zhu
Ruiming Rong
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2014
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-014-0224-z

Other articles of this Issue 1/2014

Journal of Translational Medicine 1/2014 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
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.