Ischemic and toxic acute renal failure remain important causes of morbidity and mortality in hospitalized patients and greatly increase the expense of care. ATP production in the kidney proximal tubule, a major site of injury during acute renal failure, is especially sensitive to mitochondrial dysfunction because, depending on the segment, glycolysis is absent or minimal in proximal tubule cells. When isolated proximal tubules are subjected to hypoxia/reoxygenation under conditions relevant to ischemia/reperfusion in vivo, they develop a severe energetic deficit characterized by persistent ATP depletion and impaired recovery of mitochondrial membrane potential during reoxygenation, which plays a pivotal role in tubule cell survival and recovery from the insult. The energetic deficit can be ameliorated by specific, supplemental citric acid cycle metabolites. Work during the current funding period has shown that the deficit cannot be readily explained by abnormalities of mitochondrial electron transport, the adenine nucleotide translocase or the F1FO-ATPase. Instead, it appears to be primarily attributable to mitochondrial de-energization produced by nonesterified fatty acids (NEFA). Lowering NEFA availability restores mitochondrial membrane potential and ATP production and is a major mechanism for the benefit provided by the supplemental substrates. To further test this hypothesis and investigate the mechanisms involved and the implications for tubule cell injury, we plan to: 1) Clarify the role of NEFA shuttling on mitochondrial inner membrane anion carriers in the mediation of NEFA-induced dissipation of mitochondrial membrane potential. 2) Determine whether UCP2 is involved in the NEFA effects. 3) Assess the NEFA lowering efficacy of agents that restore mitochondrial membrane potential. 4) Quantify the free fatty acid levels mediating dissipation of mitochondrial membrane potential. 5) Assess the magnitude of the NEFA- induced proton leak and the role of NEFA in respiratory inhibition. 6) Test whether NEFA-induced dissipation of mitochondrial membrane potential accounts for the matrix condensation characteristic of the energetic deficit and whether condensation itself further impairs mitochondrial function. 7) Further investigate the role of mitochondrial reactive oxygen species production and its modification by NEFA in the energetic deficit. 8) Characterize expression of the mitochondrial permeability transition in the tubules, its modification by NEFA, and its contribution to progression of mitochondrial dysfunction. These studies are relevant to understanding and treating ischemic acute renal failure and preserving kidneys and other organs for transplantation and to the basic understanding of the critical role that mitochondria are now recognized to play during both necrotic and apoptotic cell death in all cell types.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK034275-25
Application #
8325924
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
1984-07-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
25
Fiscal Year
2012
Total Cost
$373,232
Indirect Cost
$121,395
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Parekh, Dipen J; Weinberg, Joel M; Ercole, Barbara et al. (2013) Tolerance of the human kidney to isolated controlled ischemia. J Am Soc Nephrol 24:506-17

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