Inhibitors of poly (ADP‐ribose) synthetase reduce renal ischemia‐reperfusion injury in the anesthetized ratin vivo

Abstract

The activation of poly (ADP-ribose) synthetase (PARS) subsequent to DNA damage caused by reactive oxygen or nitrogen species has been implicated in several pathophysiological conditions, including ischemia-reperfusion injury and shock. The aim of this study was to investigate whether PARS inhibitors could provide protection against renal ischemia-reperfusion injury in the rat in vivo. Male Wistar rats were subjected to 45 min bilateral clamping of the renal pedicles, followed by 6 h reperfusion (control animals). Animals were administered the PARS inhibitors 3-aminobenzamide, 1, 5-dihydroxyisoquinoline, or nicotinamide during the reperfusion period. Ischemia, followed by reperfusion, produced significant increases in plasma concentrations of urea, creatinine, and fractional excretion of Na(+) (FE(Na)) and produced a significant reduction in glomerular filtration rate (GFR). However, administration of the PARS inhibitors significantly reduced urea and creatinine concentrations, suggesting improved renal function. The PARS inhibitors also significantly increased GFR and reduced FE(Na), suggesting the recovery of both glomerular and tubular function, respectively, with a more pronounced recovery of tubular function. In kidneys from control animals, histological examination revealed severe renal damage and immunohistochemical localization demonstrated PARS activation in the proximal tubule. Both renal damage and PARS activation were attenuated by administration of PARS inhibitors during reperfusion. Therefore, we propose that PARS activation contributes to renal reperfusion injury and that PARS inhibitors may be beneficial in renal disorders associated with oxidative stress-mediated injury.

Evaluation of the Efficacy of Ginger, Arabic Gum, andBoswelliain Acute and Chronic Renal Failure

“…These mechanisms may include (but are not limited to) the generation of ROS and reactive nitrogen species, an enhanced formation of nitric oxide, modification of endogenous lipoxin generation, or the activation of the nuclear enzyme poly(ADP-ribose) polymerase. 57 In conclusion, it is clear that oxidative stress plays a crucial role in the development of adenine-induced renal failure and the more the potent antioxidant, the more the renoprotective effect. It is also clear that ginger is the most potent renoprotective agent against adenineinduced renal failure in this study followed by AG.…”

Increased expression and activation of poly(ADP-ribose) polymerase (PARP) contribute to retinal ganglion cell death following rat optic nerve transection

“…Downstream events of massive PARP activation are NAD + depletion resulting in depletion of cellular ATP and subsequent necrotic-type cell death. 41 Inhibition of PARP activity using benzamide analogs, nicotinamide, benzopyrones or isoquinoline derivatives 36 has been demonstrated to attenuate ischemia-reperfusion injury in various models of transient cerebral, 10,37,38 heart, 40 renal, 3 and retinal ischemia. 24 In addition, PARP inhibition has been shown to protect from glutamate-and MPTP-induced neurotoxicity.…”

“…For Western blot analysis, retinae were dissected at different time points after ON transection (3,12,24, 72 h, 7 days; n=4 for each time point). Retinae of sham-operated animals served as controls.…”

Renal Hypoxia and Dysoxia After Reperfusion of the Ischemic Kidney

“…DNA repair processes such as poly(ADP-ribose) polymerase (PARP) activation may aggravate endothelial dysfunction and tubular damage (138,139). PARP-1 activation has been implicated in endothelial injury, as illustrated by finding a reduced number of adherent and rolling leukocyte as well as red blood cell trapping in PARP-1 -/-mice after I/R (140).…”