Abstract
BackgroundNovel 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 FindingsIn 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.ConclusionThese 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.
Highlights
Kidney transplantation is the best choice for patients with endstage kidney disease
These data show the protective role of poly- (ADP-ribose) polymerase (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 PI3-K-Akt pathways to cytoprotective direction
Earlier data demonstrated that higher oxidative stress markers in the serum of transplanted patients generally result in less functional kidney indicating the significance of oxidative stress in the decline of graft function [6]
Summary
Kidney transplantation is the best choice for patients with endstage kidney disease. Due to cellular and humoral immune response, acute kidney damage may be an important cause for graft loss [1]. Allograft damage may be caused by leukocyte infiltration, recruitment of neutrophils and monocytes on activated endothelial cells contributing to tubular interstitial inflammation and oxidative stress. These processes lead to cell death and chronic dysfunction [5]. 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. We raised the possibility that PARP inhibition curbs cell death pathways and shifts kinase signaling to improved graft survival
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