Response to “ROS, P53 and ischemic acute kidney injury in diabetic models”

We thank Wei and colleagues for their interest¹ in our report² on the susceptibility of diabetic models to renal ischemia-reperfusion injury (IRI) that involves hyperglycemia, p53 and mitochondrial pathway of apoptosis. We agree that reactive oxygen species (ROS) might be an important factor for heightened p53 activation by IRI in diabetic kidneys. ROS is produced in diabetic tissues and may activate p53 by inducing DNA damage and other relevant mechanisms. Consistently, we showed p53 activation in high glucose incubated renal tubular cells and in kidney tissues of some diabetic animals (and, intriguingly, not in others)². However, in addition to ROS, there are other pathogenic factors in diabetes, including protein glycation and acetylation etc.³, that may also lead to heightened p53 activation.

It is indeed important to identify the cell types with heightened p53 activation. We showed that ablation of proximal tubule (PT)-p53 attenuated IRI sensitivity of diabetic mice. Of note, the attenuation was incomplete, likely because: 1) p53 in other cell types may contribute to the IRI sensitivity, and 2) our model achieved p53 ablation in ~80% PTs and the remaining 20% PT cells may still mount p53 activation for IRI². Global p53 ablation sensitized mice to IRI⁴, but PT-specific p53 ablation suppressed IRI^{5, 6}, unveiling opposing roles of p53 in different cells within the kidney. Even in the same cells, p53 may initially protect, and only when the injury is prolonged and overwhelming, it turns on the mechanism of cell death7.