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Am J Physiol Renal Physiol 282: F981-F990, 2002. First published January 29, 2002; doi:10.1152/ajprenal.00301.2001
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Vol. 282, Issue 6, F981-F990, June 2002

Mitochondrial dysfunction is an early event in high-NaCl-induced apoptosis of mIMCD3 cells

Luis Michea1, Christian Combs2, Peter Andrews3, Natalia Dmitrieva1, and Maurice B. Burg1

1 Laboratory of Kidney and Electrolyte Metabolism and 2 Light Microscopy Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-1603; and 3 Department of Cell Biology, Georgetown University Medical Center, Washington, District of Columbia 20002

Raising osmolality to 700 mosmol/kgH2O by the addition of NaCl rapidly kills most murine inner renal medullary collecting duct cells (mIMCD3), but they survive at 500 mosmol/kgH2O. At 300 and 500 mosmol/kgH2O, NADH autofluorescence is present in a mitochondria-associated, punctate perinuclear pattern. Within 45 s to 30 min at 700 mosmol/kgH2O, the autofluorescence spreads diffusely throughout the cell. This correlates with mitochondrial membrane depolarization, measured as decreased tetramethylrhodamine methyl ester perchlorate (TMRM) fluorescence. Mitochondrial dysfunction should increase the cellular ADP/ATP ratio. In agreement, this ratio increases within 1-6 h. Mitochondrial morphology (transmission electron microscopy) is unaffected, but nuclear hypercondensation becomes evident. Progressive apoptosis occurs beginning 1 h after osmolality is raised to 700, but not to 500, mosmol/kgH2O. General caspase activity and caspase-9 activity increase only after 6 h at 700 mosmol/kgH2O. The mitochondrial Bcl-2/Bax ratio decreases within 1-3 h, but no cytochrome c release is evident. The mitochondria contain little p53 at any osmolality. Adding urea to 700 mosmol/kgH2O does not change NADH or TMRM fluorescence. We conclude that extreme acute hypertonicity causes a mitochondrial dysfunction involved in the initiation of apoptosis.

caspase; endonuclease G; cytochrome c; mitochondria membrane potential; murine inner medullary collecting duct; sodium chloride


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