PMID- 24312605
OWN - NLM
STAT- MEDLINE
DCOM- 20140927
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 12
DP  - 2013
TI  - PARP inhibition attenuates acute kidney allograft rejection by suppressing cell 
      death pathways and activating PI-3K-Akt cascade.
PG  - e81928
LID - 10.1371/journal.pone.0081928 [doi]
LID - e81928
AB  - BACKGROUND: Novel immunosuppressive therapy facilitates long term allograft 
      survival, but acute tubular necrosis and ischemia-reperfusion during 
      transplantation can compromise allograft function. These processes are related to 
      oxidative stress which activates poly- (ADP-ribose) polymerase (PARP) 
      contributing to the activation of cell death pathways. Here we raised the 
      possibility that PARP inhibition curbs cell death pathways and shifts kinase 
      signaling to improved graft survival. METHODS FINDINGS: In an acute rat kidney 
      rejection model, we provided evidence that the PARP inhibitor 
      4-hydroxy-quinazoline (4OHQ) attenuates rejection processes initiated 
      oxidative/nitrosative stress, nuclear poly-ADP-ribosylation and the 
      disintegration of the tubulo-interstitial structures. The PARP inhibitor 
      attenuated rejection processes induced pro-apoptotic pathways by increasing 
      Bcl-2/Bax ratio and suppressing pro-apoptotic t-Bid levels. In transplanted 
      kidneys, the cell death inducing JNK1/2 is normally activated, but PARP 
      inhibition suppressed this activation with having only modest effects on ERK1/2 
      and p38 MAP kinases. In untreated transplanted kidneys, no significant 
      alterations were detected in the cytoprotective PI-3K-Akt pathway, but the PARP 
      inhibitor significantly activated Akt (by S473 phosphorylation) and suppressed 
      GSK-3beta, as well as activated acute NF-kappaB activation contributing to graft 
      protection. CONCLUSION: These data show the protective role of PARP inhibition on 
      graft survival by attenuating poly-ADP-ribosylation, oxidative stress, 
      suppressing pro-apoptotic and increasing anti-apoptotic protein level, and by 
      shifting MAP kinases and PI-3-K-Akt pathways to cytoprotective direction. Thus, 
      addition of PARP inhibitors to standard immunosuppressive therapies during kidney 
      transplantation may provide increased protection to prolong graft survival.
FAU - Kalmar-Nagy, Karoly
AU  - Kalmar-Nagy K
AD  - Department of Surgery, University of Pecs Medical School, Pecs, Hungary.
FAU - Degrell, Peter
AU  - Degrell P
FAU - Szabo, Aliz
AU  - Szabo A
FAU - Sumegi, Katalin
AU  - Sumegi K
FAU - Wittmann, Istvan
AU  - Wittmann I
FAU - Gallyas, Ferenc Jr
AU  - Gallyas F Jr
FAU - Sumegi, Balazs
AU  - Sumegi B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131203
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (NF-kappa B)
RN  - 0 (Poly(ADP-ribose) Polymerase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Allografts
MH  - Animals
MH  - Cell Death/drug effects
MH  - Cytoprotection/drug effects
MH  - Enzyme Inhibitors/pharmacology/therapeutic use
MH  - Graft Rejection/drug therapy/*pathology/*prevention & control
MH  - Immunosuppressive Agents/pharmacology/therapeutic use
MH  - Kidney/drug effects/pathology
MH  - Kidney Transplantation/*adverse effects
MH  - Male
MH  - NF-kappa B/metabolism
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - *Poly(ADP-ribose) Polymerase Inhibitors
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Proto-Oncogene Proteins c-bcl-2/metabolism
MH  - Rats
MH  - Signal Transduction/*drug effects
PMC - PMC3849354
COIS- Competing Interests: Co-author Ferenc Gallyas Jr is a PLOS ONE Editorial Board 
      member. This does not alter the authors' adherence to all the PLOS ONE policies 
      on sharing data and materials.
EDAT- 2013/12/07 06:00
MHDA- 2014/09/28 06:00
PMCR- 2013/12/03
CRDT- 2013/12/07 06:00
PHST- 2013/07/26 00:00 [received]
PHST- 2013/10/17 00:00 [accepted]
PHST- 2013/12/07 06:00 [entrez]
PHST- 2013/12/07 06:00 [pubmed]
PHST- 2014/09/28 06:00 [medline]
PHST- 2013/12/03 00:00 [pmc-release]
AID - PONE-D-13-30509 [pii]
AID - 10.1371/journal.pone.0081928 [doi]
PST - epublish
SO  - PLoS One. 2013 Dec 3;8(12):e81928. doi: 10.1371/journal.pone.0081928. eCollection 
      2013.