Significant Reduction of Murine Renal Ischemia-Reperfusion Cell Death Using the Immediate-Acting PrC-210 Reactive Oxygen Species Scavenger.

Abstract

Background.Ischemia-reperfusion (IR) injury remains a significant problem for all solid organ transplants; thus, an important unmet need in transplantation is the prevention of IR injury. PrC-210 has demonstrated superior prevention of reactive oxygen species damage in several preclinical studies as a free radical scavenger. Here, we describe its profound efficacy in suppressing IR injury in a murine model of kidney IR injury.Methods.C57/B6 mice underwent laparotomy with the left renal pedicle occluded for 30 minutes to induce IR injury. Right nephrectomy was performed at the time of surgery. Mice received a single systemic dose of the PrC-210, PrC-211, or PrC-252 aminothiols 20 minutes before IR injury. Twenty-four hours following IR injury, blood and kidney tissue were collected for analysis. Kidney caspase-3 level (a marker of cell death), direct histological analysis of kidneys, and serum blood urea nitrogen (BUN) were measured in animals to assess reactive oxygen species scavenger protective efficacies.Results.A single systemic PrC-210 dose 20 minutes before IR injury resulted in significant reductions in (1) IR-induced kidney caspase level (P < 0.0001); caspase was reduced to levels not significantly different than control caspase levels seen in unperturbed kidneys, (2) IR-induced renal tubular injury scores (P < 0.0001); brush border loss and tubular dilation were markedly reduced, and (3) serum BUN compared with control IR injury kidneys (P < 0.0001). The ranked protective efficacies of PrC-210 > PrC-211 >> PrC-252 paralleled previous radioprotection studies of the molecules.Conclusions.A single PrC-210 dose, minutes before the IR insult, profoundly reduced caspase, renal tubular injury, and serum BUN in mice exposed to standard kidney IR injury. These findings support further development of the PrC-210 molecule to suppress or prevent IR injury in organ transplant and other IR injury settings.