Grant: Project Grant

A sudden kidney failure is a frequent medical complication of hospitalized patients. This condition, called acute kidney injury (AKI), is often associated with an increased length of hospital stay, the development of chronic kidney disease, and increased risk of mortality. Unfortunately, there is no specific therapy for hospital acquired AKI. In this context, doctors are in dire need of new treatments that they could administer to their patients while permanent kidney damage can be prevented. The current research proposal addresses this need by building upon our recent discovery that specialized cells in the kidney induce local inflammation through the activation of a receptor, called P2Y14, located on their surface. This inflammatory cascade leads to kidney damage. Using pre-clinical animal laboratory models, we found that inhibition of the P2Y14 receptor reduces kidney inflammation following a surgery, and preserves kidney function, therefore alleviating AKI. The current proposal will use two distinct models of AKI, induced by: 1) a reduction of oxygen delivery to the kidneys, a condition that mimics what happens to the kidneys during an open-heart surgery; and 2) an infection (also called septicemia). We will elucidate the cellular mechanisms that participate in the protection of a P2Y14 receptor blocker against the severity of AKI and its progression to chronic kidney disease. At the completion of this work, we will have dissected the cellular and inter-cellular pathways that govern the participation of the pro-inflammatory P2Y14 receptor in the onset of AKI, and have identified means to block its action. The overall objectives of our research are to provide an in-depth understanding of the contribution of the P2Y14 receptor in AKI of different origins, and provide an informed basis upon which to assess situations in which blocking the P2Y14 receptor will be most efficacious to treat AKI patients in the future.