PMID- 23769029
OWN - NLM
STAT- MEDLINE
DCOM- 20140127
LR  - 20211203
IS  - 1873-2623 (Electronic)
IS  - 0041-1345 (Linking)
VI  - 45
IP  - 5
DP  - 2013 Jun
TI  - The effect of mTOR-inhibition on NF-kappaB activity in kidney ischemia-reperfusion 
      injury in mice.
PG  - 1708-14
LID - S0041-1345(13)00328-X [pii]
LID - 10.1016/j.transproceed.2013.02.110 [doi]
AB  - Kidney ischemia-reperfusion injury (IRI) is associated with a robust inflammatory 
      response, which is regulated by nuclear factor-kappaB (NF-kappaB), mainly its 
      heterodimeric form p65/p50. Considering immunomodulatory properties of mammalian 
      target of rapamycin (mTOR) inhibitors, the effect of everolimus on NF-kappaB 
      activation in kidney IRI was determined in this study. IRI was induced in C57/BL6 
      mice by clamping both renal pedicles for 45 minutes. Application of everolimus 
      (0.25 mg/kg bw subcutaneously daily) was started one day before IRI induction. 
      Both everolimus-treated and nontreated mice were sacrificed at several times 
      starting at 30 minutes and finishing on day 7 after IRI induction. The NF-kappaB 
      activity, proinflammatory cytokines IL-1beta, TNF-alpha, and anti-inflammatory cytokine 
      IL-10 production were determined in kidneys. Compared with nontreated animals, 
      everolimus-treated animals showed significantly increased TNF-alpha (2741.6 +/- 201.72 
      pg/mg; 1925 +/- 185.81 pg/mg, P < .05) and IL-1beta (11.47 +/- 1.2 pg/mg; 4.3 +/- 0.13 
      pg/mg, P < .01) production on day 2 after IRI induction accompanied by 
      significantly greater NF-kappaB/DNA binding activity and p65 nuclear expression (P < 
      .01). Two hours after IRI induction, everolimus-treated animals showed 
      significantly increased IL-1beta mRNA expression (P < .05) followed by increased 
      IL-1beta protein concentrations when compared with nontreated animals measured 6 
      hours after IRI induction (11.71 +/- 1.5 pg/mg; 7.5 +/- 1.11 pg/mg, P < .01). Both 
      experimental groups showed increased NF-kappaB/DNA binding activity at 7 days after 
      IRI induction. Significantly increased nuclear p65 expression was measured in 
      nontreated animals (P < .01), whereas everolimus-treated hosts showed 
      significantly increased nuclear RelB expression (P < .01). These data suggested 
      that everolimus potentiated innate immunity in the early phase of IRI, 
      stimulating the production of NF-kappaB-driven proinflammatory cytokines such as 
      TNF-alpha and IL-1beta. The NF-kappaB activity was potentiated under m-TOR inhibition during 
      kidney IRI, implicating a possible beneficial role of alternative NF-kappaB 
      activation during the repair phase.
CI  - Copyright (c) 2013 Elsevier Inc. All rights reserved.
FAU - Kezic, A
AU  - Kezic A
AD  - School of Medicine, University of Belgrade, Serbia; Clinic of Nephrology, 
      Clinical Center of Serbia, Belgrade, Serbia. aleksandrakezic@yahoo.com
FAU - Becker, J U
AU  - Becker JU
FAU - Thaiss, F
AU  - Thaiss F
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Transplant Proc
JT  - Transplantation proceedings
JID - 0243532
RN  - 0 (Cytokines)
RN  - 0 (DNA Primers)
RN  - 0 (NF-kappa B)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - Cytokines/metabolism
MH  - DNA Primers
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - NF-kappa B/*metabolism
MH  - Real-Time Polymerase Chain Reaction
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
EDAT- 2013/06/19 06:00
MHDA- 2014/01/28 06:00
CRDT- 2013/06/18 06:00
PHST- 2012/12/15 00:00 [received]
PHST- 2013/02/07 00:00 [revised]
PHST- 2013/02/27 00:00 [accepted]
PHST- 2013/06/18 06:00 [entrez]
PHST- 2013/06/19 06:00 [pubmed]
PHST- 2014/01/28 06:00 [medline]
AID - S0041-1345(13)00328-X [pii]
AID - 10.1016/j.transproceed.2013.02.110 [doi]
PST - ppublish
SO  - Transplant Proc. 2013 Jun;45(5):1708-14. doi: 10.1016/j.transproceed.2013.02.110.