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1 Division of Nephrology, Veterans Affairs Ann Arbor Healthcare System and University of Michigan, Ann Arbor, MI, USA; Division of Nephrology and Hypertension, Department of Internal Medicine, University Hospital Essen, Essen, Nordrhein-Westfalen, Germany
2 Division of Nephrology and Hypertension, Department of Internal Medicine, University Hospital Essen, Essen, Nordrhein-Westfalen, Germany
3 Division of Nephrology, Veterans Affairs Ann Arbor Healthcare System and University of Michigan, Ann Arbor, MI, USA
* To whom correspondence should be addressed. E-mail: wnberg{at}umich.edu.
Kidney proximal tubules exhibit decreased ATP and reduced, but not absent, mitochondrial
membrane potential (DeltaPsi(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 ATP synthase
and adenine nucleotide translocase activities. Addition of oleate to permeabilized tubules
produced concentration-dependent decreases of DeltaPsi(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 bovine serum albumin (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 DeltaPsi(m) when the duration of hypoxia was increased to
120 min. In intact tubules, the protective substrate combination of 
-ketoglutarate+malate
(KG/MAL) increased ATP 3-4 fold, 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 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
KG/MAL.
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