Renal
ischemia-reperfusion (I/R) injury, which is unavoidable in
renal transplantation, frequently influences both short- and long-term allograft survival. Despite decades of laboratory and clinical investigations, and the advent of
renal replacement therapy, the overall mortality rate due to acute tubular injury has changed little. I/R-induced DNA damage results in p53 activation in proximal tubule cells (PTC), leading to their apoptosis. Therefore, we examined the
therapeutic effect of temporary p53 inhibition in two rat
renal transplantation models on structural and functional aspects of injury using intravital two-photon microscopy. Nephrectomized Sprague-Dawley rats received syngeneic left
kidney transplantation either after 40 min of intentional
warm ischemia or after combined 5-h cold and 30-min
warm ischemia of the graft. Intravenously administrated
siRNA for p53 (siP53) has previously been shown to be filtered and reabsorbed by proximal tubular epithelial cells following the
warm ischemia/
reperfusion injury in a renal clamp model. Here, we showed that it was also taken up by PTC following 5 h of cold ischemia. Compared to saline-treated recipients, treatment with siP53 resulted in conservation of renal function and significantly suppressed the I/R-induced increase in serum
creatinine in both
kidney transplantation models. Intravital two-photon microscopy revealed that siP53 significantly ameliorated structural and functional damage to the kidney assessed by quantification of tubular cast formation and the number of apoptotic and necrotic tubular cells and by evaluation of blood flow rate. In conclusion, systemic administration of
siRNA for p53 is a promising new approach to protect kidneys from I/R injury in
renal transplantation.