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

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PROJECT SUMMARY/ABSTRACT This proposal includes a five-year research career development program to study classical and alternative renin-angiotensin system (RAS) dysregulation in sepsis-associated acute kidney injury (SA-AKI). The candidate is currently an Assistant Professor 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. Current therapy is limited to supportive care and kidney replacement therapy. Recent evidence suggests sepsis causes a disruption in angiotensin converting enzyme (ACE) and ACE2 that could severely dysregulate the RAS. This disruption may ultimately result in local excess of the proinflammatory, classical RAS and deficiencies in the counter-regulatory, anti-inflammatory alternative RAS (Alt-RAS). An intra-renal RAS, operating independently from the circulatory RAS, may drive pathophysiology and urinary RAS biomarkers have been proposed as surrogate markers of intra-renal RAS activation. Using a bedside-to-bench approach, our overall objective is to quantify the classical and Alt-RAS disturbances present at the circulatory and tissue level in SA-AKI, and evaluate the relationship between the extent of this disturbance and major adverse kidney events. Our central hypothesis is that a deficiency of the regenerative RAS, or Alt-RAS, exists relative to the classical RAS in SA-AKI at the circulatory and tissue level, and that the degree of this imbalance differentially associates with outcomes in patients with SA-AKI. We propose three specific aims to accomplish this: (1) To determine the relationship between RAS dysregulation, kidney biomarkers of tubular injury and function, and major adverse kidney events within 30 days (MAKE-30) in SA-AKI, (2) To assess the relationship between urinary biomarkers of intra-renal RAS activation and MAKE outcomes out to one year in critically ill patients with SA-AKI and heterogenous AKI, and (3) To test the hypothesis that the kidney RAS peptide metabolome and receptor expression profile shift to a regenerative or Alt-RAS deficiency in a murine model of SA-AKI, and that the degree of Alt-RAS deficiency (relative to classical RAS) corresponds to the degree of 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, and learning pre-clinical models of SA-AKI. This proposal supports the mission of NIDDK by furthering the understanding of SA- AKI, a leading cause of AKI and kidney complications impacting the public’s health and quality of life.