Renal Oxygenation and Mitochondrial Function in AKI

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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 primary and/or secondary changes in mitochondrial function and morphology in sepsis associated AKI that lead to inefficient oxygen utilization by the kidney. The proposal also aims to determine the effects of mitochondrial dysfunction and elevated oxygen utilization in the kidney on overall renal function and kidney injury in the setting of 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 physiological techniques such as whole animal kidney clearance, renal blood flow and micropuncture and molecular techniques to assess mitochondrial bioenergetics, ATP, reactive oxygen species generation and electron microscopy to assess mitochondrial morphology and dynamics. These investigations will provide important insights into hemodynamic and non-hemodynamic factors in the pathogenesis of sepsis-associated AKI and identify specific mechanistic pathways and novel therapeutic targets. The insights obtained will be will be valuable beyond the model studied given the wide-spread implications of mitochondrial dysfunction in kidney disease.