title: PARP inhibition attenuates acute kidney allograft rejection by suppressing cell death pathways and activating PI-3K-Akt cascade.
abstract: 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.
  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-3β, as well as activated acute NF-kappaB activation contributing to graft protection.
  
  
  CONCLUSIONS
  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.
authors: Department of Surgery, University of Pecs Medical School, Pecs, Hungary.
authors: Karoly
authors: K
authors: Kalmar-Nagy
authors: Peter
authors: P
authors: Degrell
authors: Aliz
authors: A
authors: Szabo
authors: Katalin
authors: K
authors: Sumegi
authors: Istvan
authors: I
authors: Wittmann
authors: Ferenc
authors: F
authors: Gallyas
authors: Balazs
authors: B
authors: Sumegi
mesh_terms: D064591:Allografts; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006084:Graft Rejection / Q000188:drug therapy / Q000473:pathology* / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt