Protective pathways in sepsis-induced renal injury

About This Grant

Background and Innovation: Acute kidney injury (AKI) is a complex pathological state associated with highly heterogenous outcomes, ranging from full recovery to death. Various underlying factors contribute to the wide- ranging disease trajectories, including aging, inflammation, and prior exposure to AKI. One class of molecules broadly applicable to such disease susceptibility is polyamines. Polyamines are involved in a variety of fundamental biological processes such as protein synthesis, cellular proliferation, and DNA repair. The importance of polyamine homeostasis is also implicated in various forms of kidney diseases. Our ongoing work indicates that Antizyme Inhibitor 1 (AZIN1), a positive regulator of polyamine biosynthesis, plays a significant role in determining the outcome of AKI. In response to tissue injury and inflammation, AZIN1 undergoes adenosine-to-inosine posttranscriptional modification (A-to-I editing). Our data suggest that AZIN1 A-to-I editing is conducive to recovery as it augments the polyamine anabolic pathway and enhances metabolic flexibility. Through various sequencing methods and murine models of AZIN1 A-to-I editing, this proposal will examine the vital role of AZIN1 A-to-I editing and polyamines in renal health and disease. Furthermore, using multiple murine models of AKI, we aim to build a genome-wide, time-anchored map of A-to-I editing with the goal of establishing a framework for molecular staging in kidney disease. Significance and Impact to Veterans Healthcare: The mortality rate associated with AKI in veterans remains exceedingly high, with over 1 in 4 veterans dying within a year from the onset of AKI. Our proposed study aims to address knowledge gaps at the molecular level to enhance post-AKI outcomes. Path to translation/implementation: During the current funding period, we have identified AZIN1 A-to-I editing as a molecular signature enabling the stratification of AKI timeline and recovery potential. This renewal proposal is therefore set out to test this concept and conduct proof-of-concept studies, transitioning from VHA/ORD research priority T0-1 to T0-2.