Regulation of exosome release and its role in acute kidney injury.

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Project Summary/Abstract Acute kidney injury (AKI) is a condition that results in an abrupt decrease in renal function. AKI is associated with morbidity, mortality, and health care costs. Unfortunately, the incidence rate of AKI in hospitalized patients is still increasing. Furthermore, incomplete recovery from AKI leads to chronic kidney disease (CKD), and in some cases, end-stage renal disease, which is also associated with significant morbidity, mortality, and cost. To date, we lack methods to predict which patients will suffer long-term sequelae from AKI and treatments for AKI except for supportive care. Exosomes, nanometer-sized extracellular vesicles have been recognized as a fingerprint of the cellular states, as well as a mode of intercellular communication in physiological and pathophysiological conditions. We recently identified the role of exosomes in renal cell tubule growth, which is recapitulated and required for renal tubule regrowth from damaged kidneys in AKI. Given the lack of clinical therapies and the critical links between AKI and CKD, we will focus on whether exosomes released in AKI is an endogenous recovery mechanism, which might be a tool to both treat AKI and prevent CKD. This proposal investigates the role of urinary exosome proteins in recovery following AKI: Aim 1 will investigate how exosomes are produced, and their impact on in vitro healing and tubule growth in the tubules-on-dish. We will manipulate the gene expression and/or mutation of regulatory proteins in exosome biogenesis, in order determine the effects of the manipulation in renal cell tubule growth. Aim 2 will investigate the role of controlled exosome release in in vivo mouse models of AKI. Using longitudinal analyses of urinary exosomes released during AKI, viral delivery of exosome-incompetent target proteins, and engineered exosome-mediated protein delivery, we will investigate the role of exosome-loaded proteins in renal tubule regrowth. Signal transfer via exosomes within proximal tubules and proximal-to-distal tubules during AKI will be determined as well. The results of these studies will determine if exosome release is an endogenous recovery mechanism following AKI, and may generate therapeutic targets, as well as candidate prognostic biomarkers for future studies in patients suffering from AKI.