Renal Metabolism in AKI

PROJECT SUMMARY Acute kidney injury (AKI) in the setting of sepsis is frequently observed and is a significant clinical problem with high levels of morbidity and mortality. One of the major barriers to the progress in the field is the lack of understanding of the pathogenesis of AKI in this setting. The specific aims of this proposal is to investigate the changes in kidney metabolism in sepsis associated AKI that impact injury and recovery of kidney tubules which are the primary site of injury in sepsis. The research strategy is to employ a comprehensive investigative approach for an integrative understanding of pathogenesis of sepsis associated AKI, using the clinically relevant cecal ligation and puncture model of sepsis. The methods will include molecular techniques to assess tubular metabolism, mitochondrial bioenergetics, ATP, reactive oxygen species generation and electron microscopy to assess mitochondrial morphology and dynamics, metabolic imaging and physiological techniques such as in-vivo glomerular and tubular function at a single nephron and whole kidney level. These investigations will provide important mechanistic insights into the pathogenesis of sepsis-associated AKI and identify novel therapeutic targets. The insights obtained will be valuable beyond the model studied given the wide-spread implications of metabolic dysfunction in kidney disease.