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 te pathogenesis of the renal failure in this setting.
The specific aims of this pilot proposal is to investigate the primary and/or secondary changes in mitochondrial function and morphology in sepsis associated AKI that leads to inefficient oxygen utilization by the kidney using a rodent model of cecal ligation and puncture. 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. 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 and 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, which will be pursued in further details in a subsequent proposal for independent funding. The insights obtained will be will be valuable beyond the model studied given the universal implications of mitochondrial dysfunction. The short-term goal of the applicant is to obtain this R03 pilot grant to build upon the interesting and novel results obtained so far with the support of the K08 and O'Brien Center pilot and feasibility grant to continue the trajectory of progress to a competitive R01 application The long-term objective is to develop an independent area of expertise in the regulation of renal hemodynamics, oxygenation and mitochondrial function in renal physiology and pathophysiology.

Public Health Relevance

Acute kidney injury in the setting of sepsis is common in critically ill patients and is a significant medical problem with a poor prognosis. Lack of understanding of the mechanisms that lead to kidney injury has been a major barrier to progress in this area and improvement of outcomes in patients. This proposal aims to understand the mechanisms leading to kidney injury and has the potential to identify novel therapeutic targets for patients with sepsis associated kidney injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK101841-01A1
Application #
8824138
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2015-07-01
Project End
2017-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Hepokoski, Mark; Englert, Joshua A; Baron, Rebecca M et al. (2017) Ventilator-induced lung injury increases expression of endothelial inflammatory mediators in the kidney. Am J Physiol Renal Physiol 312:F654-F660
Bullen, Alexander; Liu, Zhi Zhao; Hepokoski, Mark et al. (2017) Renal Oxygenation and Hemodynamics in Kidney Injury. Nephron 137:260-263
Thomas, Joanna L; Pham, Hai; Li, Ying et al. (2017) Hypoxia-inducible factor-1? activation improves renal oxygenation and mitochondrial function in early chronic kidney disease. Am J Physiol Renal Physiol 313:F282-F290
Liu, Zhi Zhao; Bullen, Alexander; Li, Ying et al. (2017) Renal Oxygenation in the Pathophysiology of Chronic Kidney Disease. Front Physiol 8:385
Nourbakhsh, Noureddin; Singh, Prabhleen (2014) Role of renal oxygenation and mitochondrial function in the pathophysiology of acute kidney injury. Nephron Clin Pract 127:149-52