Novel mitochondrial protective properties of annexin A1

ABSTRACT Acute kidney injury (AKI) is one of the most common forms of perioperative organ injury occurring in up to 30% of post-surgical patients, and it significantly increases morbidity and mortality. A number of vascular and transplant surgeries require interruption of blood flow to the kidney, rendering the kidney ischemic and causing significant metabolic stress. The timing of this kidney insult is known; thus, the possibility exists to intervene to protect the kidney. However, no treatment options exist to prevent or treat post-surgical AKI. The development of kidney protective therapeutics has the potential to greatly improve outcomes in the millions of people who undergo surgical operations and kidney transplants each year. Our long-term goal is to develop kidney protective therapeutics to limit post-operative and post- transplant AKI. One such therapy could be to limit mitochondrial stress as the kidney is particularly susceptible to mitochondrial stress due to its high metabolic demands. As such, the development of mitochondrial protectants that could limit post-surgical and transplant AKI holds considerable promise. Along these lines, our group has developed a novel peptide mimetic of the parent annexin A1 molecule that in our preliminary data shows that it can ameliorate ischemic kidney injury in mice by limiting kidney tubular cell death and upregulating sirtuin-3 (SIRT3) to augment mitochondrial function. Despite the promise of our therapeutic to limit ischemic kidney injury, the novel mechanism by which it protects the kidney is not known. Thus, the objectives of this proposal are to determine the mechanism through which our annexin A1 mimetic augments mitochondrial function and metabolism and limits kidney tubular necrosis to ameliorate AKI. In this proposal, we will determine the cellular signaling pathway through which our compound upregulates SIRT3 and augments mitochondrial ATP production. We will also determine the mechanism through which it limits mitochondrial-mediated necrosis in the kidney. We will treat transgenic mice with our therapeutic and subject to both ischemia-reperfusion kidney injury and kidney cross transplantation. We will measure kidney injury and perform a variety of measures of cellular metabolism and mitochondrial function to assess efficacy and establish the mechanism of our therapeutic. Once completed, we will have defined the mechanism through which our novel therapeutic can augment mitochondrial energy production and limit mitochondria-mediated necrosis to limit post-surgical AKI. After study completion, we will be primed to pursue translational studies and further drug development. The development of our new therapeutic would not only limit postoperative and transplant AKI but also have broad implications for protection of other organs following surgery and transplantation. 1