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Am J Physiol Renal Physiol 290: F465-F477, 2006. First published September 13, 2005; doi:10.1152/ajprenal.00305.2005
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Accumulation of nonesterified fatty acids causes the sustained energetic deficit in kidney proximal tubules after hypoxia-reoxygenation

Thorsten Feldkamp,1,2 Andreas Kribben,2 Nancy F. Roeser,1 Ruth A. Senter,1 and Joel M. Weinberg1

1Division of Nephrology, Department of Internal Medicine, Veterans Affairs Ann Arbor Healthcare System and University of Michigan, Ann Arbor, Michigan; and 2Division of Nephrology and Hypertension, Department of Internal Medicine, University Hospital Essen, Essen, Germany

Submitted 29 July 2005 ; accepted in final form 31 August 2005

Kidney proximal tubules exhibit decreased ATP and reduced, but not absent, mitochondrial membrane potential ({Delta}{psi}m) during reoxygenation after severe hypoxia. This energetic deficit, which plays a pivotal role in overall cellular recovery, cannot be explained by loss of mitochondrial membrane integrity, decreased electron transport, or compromised F1F0-ATPase and adenine nucleotide translocase activities. Addition of oleate to permeabilized tubules produced concentration-dependent decreases of {Delta}{psi}m measured by safranin O uptake (threshold for oleate = 0.25 µM, 1.6 nmol/mg protein; maximal effect = 4 µM, 26 nmol/mg) that were reversed by delipidated BSA (dBSA). Cell nonesterified fatty acid (NEFA) levels increased from <1 to 17.4 nmol/mg protein during 60- min hypoxia and remained elevated at 7.6 nmol/mg after 60 min reoxygenation, at which time ATP had recovered to only 10% of control values. Safranin O uptake in reoxygenated tubules, which was decreased 85% after 60-min hypoxia, was normalized by dBSA, which improved ATP synthesis as well. dBSA also almost completely normalized {Delta}{psi}m when the duration of hypoxia was increased to 120 min. In intact tubules, the protective substrate combination of {alpha}-ketoglutarate + malate ({alpha}-KG/MAL) increased ATP three- to fourfold, limited NEFA accumulation during hypoxia by 50%, and lowered NEFA during reoxygenation. Notably, dBSA also improved ATP recovery when added to intact tubules during reoxygenation and was additive to the effect of {alpha}-KG/MAL. We conclude that NEFA overload is the primary cause of energetic failure of reoxygenated proximal tubules and lowering NEFA substantially contributes to the benefit from supplementation with {alpha}-KG/MAL.

acute renal failure; kidney; mitochondrial membrane potential


Address for reprint requests and other correspondence: J. M. Weinberg, Nephrology Division, Dept. of Internal Medicine, Rm. 1560, MSRB II, Univ. of Michigan Medical Center, Ann Arbor, MI 48109-0676 (e-mail: wnberg{at}umich.edu)




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