Alleviation of fatty acid and hypoxia-reoxygenation-induced proximal tubule deenergization by ADP/ATP carrier inhibition and glutamate.

Abstract

Kidney proximal tubules develop a severe but highly reversible energetic deficit due to nonesterified fatty acid (NEFA)-induced dissipation of mitochondrial membrane potential (DeltaPsi(m)) during reoxygenation after severe hypoxia. To assess the mechanism for this behavior, we have compared the efficacies of different NEFA for inducing mitochondrial deenergization in permeabilized tubules measured using safranin O uptake and studied the modification of NEFA-induced deenergization by inhibitors of the ADP/ATP carrier and glutamate using both normoxic tubules treated with exogenous NEFA and tubules deenergized during hypoxia-reoxygenation (H/R). Among the long-chain NEFA that accumulate during H/R of isolated tubules and ischemia-reperfusion of the kidney in vivo, oleate, linoleate, and arachidonate had strong effects to dissipate DeltaPsi(m) that were slightly greater than palmitate, while stearate was inactive at concentrations reached in the cells. This behavior correlates well with the protonophoric effects of each NEFA. Inhibition of the ADP/ATP carrier with either carboxyatractyloside or bongkrekic acid or addition of glutamate to compete for the aspartate/glutamate carrier improved DeltaPsi(m) in the presence of exogenous oleate and after H/R. Effects on the two carriers were additive and restored safranin O uptake to as much as 80% of normal under both conditions. The data strongly support NEFA cycling across the inner mitochondrial membrane using anion carriers as the main mechanism for NEFA-induced deenergization in this system and provide the first evidence for a contribution of this process to pathophysiological events that impact importantly on energetics of intact cells.

• Authors: Thorsten Feldkamp, Andreas Kribben, Nancy F Roeser, Tiffany Ostrowski, Joel M Weinberg
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 292 Issue 5 Pg. F1606-16 (May 2007) ISSN: 1931-857X [Print] United States
• PMID: 17244890 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Carrier Proteins
• Fatty Acids
• Indicators and Reagents
• Phenazines
• Oleic Acid
• Glutamic Acid
• Adenosine Diphosphate
• Adenosine Triphosphate
• Oxygen
• safranine T

Topics

• Adenosine Diphosphate (metabolism)
• Adenosine Triphosphate (metabolism)
• Animals
• Carrier Proteins (antagonists & inhibitors)
• Dose-Response Relationship, Drug
• Energy Metabolism
• Fatty Acids (pharmacology)
• Female
• Glutamic Acid (pharmacology)
• Hypoxia (metabolism)
• Indicators and Reagents (pharmacokinetics)
• Kidney Tubules, Proximal (metabolism)
• Membrane Potential, Mitochondrial (drug effects)
• Oleic Acid (administration & dosage, pharmacology)
• Oxygen (pharmacology)
• Phenazines (pharmacokinetics)
• Rabbits