Scope: Classical and Alternative Renin-Angiotensin System Dysregulation in Sepsis-Associated AKI: A Reverse Translation Approach

PROJECT SUMMARY/ABSTRACT This proposal includes a five-year research career development program focused on contributions of classical and alternative renin-angiotensin system (Alt-RAS) dysregulation in sepsis-associated acute kidney injury (SA- AKI). The candidate is currently an Assistant Professor in the Department of Pharmacy Practice and Science at the University of Kentucky College of Pharmacy. The proposal builds on the candidate’s strong background in clinical research on AKI and integrates mentorship from established investigators in sepsis, AKI, RAS therapeutics, and murine models of SA-AKI. The proposed career development activities will equip the candidate with the skills necessary to become established as an independent clinical and translational scientist conducting patient-oriented research on SA-AKI. Over 4 million patients are hospitalized annually with AKI, and sepsis is estimated to contribute to 26-50% of all cases. SA-AKI is associated with worse clinical and economic outcomes compared to non-septic AKI, and may leave patients with diminished kidney function following hospital discharge. Current therapy is limited to supportive care and renal replacement therapy. The pathophysiology of SA-AKI is complex and multifactorial, but recent evidence suggests sepsis causes a disruption in angiotensin converting enzyme (ACE), and possibly ACE2, that could severely dysregulate the RAS. This disruption in the two key enzymes of the RAS may ultimately result in local excess of the proinflammatory, classical RAS, and deficiencies in the counter- regulatory, anti-inflammatory Alt-RAS. The complexity is further increased with growing recognition of an intra- renal RAS, which may operate independently from the circulatory RAS. The overall objective of this proposal is to identify the molecular underpinnings of RAS and Alt-RAS dysfunction and their contribution to injury in SA- AKI using a reverse translation approach. We propose three specific aims to accomplish this: (1) Determine the relationship between RAS metabolomic alterations, kidney biomarkers of tubular injury and function, and major adverse kidney events (MAKE) within 30 days in patients with SA-AKI, (2) Determine the relationship between urinary biomarkers of intra-renal RAS activation and MAKE outcomes out to one year in critically ill patients with AKI, and (3) determine how SA-AKI in a murine model alters the kidney RAS metabolome and RAS receptor expression profile, and this relationship to kidney injury and intra-renal RAS activation. Career development activities that align with this research include: training in application of laboratory assays including mass spectrometry, advancement of statistical analysis skills with longitudinal data and introductory machine learning for dimensionality reduction of data, and learning a pre- clinical model of SA-AKI. This proposal supports the mission of NIDDK by furthering the understanding of SA- AKI, a leading cause of AKI and downstream kidney complications impacting the public’s health and quality of life. The research training, mentoring, and institutional environment align with the candidate’s goal of becomingan independent clinical and translational scientist conducting patient-oriented research on SA-AKI.