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1 Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
2 Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska, USA; Department of Internal Medicine, Section of Nephrology, University of Nebraska Medical Center, Omaha, Nebraska, USA
* To whom correspondence should be addressed. E-mail: bpadanilam{at}unmc.edu.
Increased generation of reactive oxygen species (ROS) and the subsequent DNA damage and excessive activation of poly (ADP-ribose) polymerase-1 (PARP-1) has been implicated in the pathogenesis of ischemic injury. We have previously demonstrated that pharmacological inhibition of PARP protects against ischemic renal injury (IRI) in rats. In order to further define the role of PARP-1 in IRI, we tested whether genetic ablation of PARP-1 attenuates tissue injury after renal ischemia. Twenty- four hours after reperfusion following 37 min of bilateral renal pedicle occlusion, the effects of the injury on renal functions in PARP-/- and PARP+/+ mice were assessed by determining glomerular filtration rate (GFR) and the plasma levels of creatinine. The levels of plasma creatinine were decreased and GFR was augmented in PARP-/- mice. Morphological evaluation of the kidney tissues showed that the extent of damage due to the injury in PARP -/- mice was less compared to their wild type counterparts. The levels of ROS and DNA damage were comparable in the injured kidneys of PARP+/+ and PARP -/- mice. PARP activity was induced in ischemic kidneys of PARP+/+ mice at 6-24 hours postinjury. At 6, 12 and 24 hours after injury, ATP levels in the PARP+/+ mice kidney declined to 28, 26 and 43% respectively while it was preserved close to normal levels in PARP-/- mice. The inflammatory cascade was attenuated in PARP-/- mice as evidenced by decreased neutrophil infiltration and attenuated expression of inflammatory molecules such as TNF-alpha, IL-1 beta and intercellular adhesion molecule-1 (ICAM-1). At 12 hours post- injury, no apoptotic cell death was observed in PARP-/- mice kidneys. However, by 24 hours post-injury, comparable number of cells underwent apoptosis in both PARP-/- and PARP+/+ mice kidneys. Thus, activation of PARP post IRI contributes to cell death most likely by ATP depletion and augmenting the inflammatory cascade in the mouse model. PARP ablation preserved ATP levels, renal functions and attenuated inflammatory response in the setting of IRI in the mouse model. PARP inhibition may have clinical efficacy in preventing the progression of ARF complications.
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