RECIPIENT:  Dr. Sylvie Breton
TITLE: Predicting and Preventing Acute Kidney Injury Associated with Cardiovascular Diseases
TECHNOLOGY TYPE: Small Molecule Drug
INDICATION: Acute Kidney Injury

DESCRIPTION:  Acute kidney injury (AKI) is a frequent complication of hospitalized patients. Unfortunately, there is no cure for this potentially deadly condition. Thus, a critical barrier to the clinical management of critically ill patients is the need for better therapeutic options to prevent/mitigate AKI. Uncontrolled inflammation is a leading cause of AKI. Injured cells release UDP-glucose (UDP-G), a danger-associated molecular pattern (DAMP) molecule, which then builds up in the kidney triggering inflammation. We showed that renal intercalated cells (ICs) detect UDP-G via the purinergic receptor P2Y14. Activation of P2Y14 by UDP-G in ICs increases the expression of chemokines that attract immune cells into the kidney. Our proposed research tests the hypothesis that blocking the UDP-glucose/P2Y14 signaling pathway in ICs alleviates renal inflammation after injury, leading to reduced incidence of AKI. In particular, we will validate novel P2Y14 antagonists for the treatment of inflammation-associated renal damage and dysfunction. We will use a pre-clinical mouse model of AKI resulting from ischemia/reperfusion injury (IRI), which induces AKI in cardiac surgery patients. Defining the action of P2Y14 antagonists in this model will provide an informed basis on which to assess the clinical settings in which these compounds would be most efficacious in preventing inflammation-associated AKI. We found that urinary UDP-G is a strong predictor of AKI in ICU patients. Thus, targeting the UDP-G/P2Y14 pathway represents a promising therapeutic approach for the prevention/mitigation of AKI.