Glycine-protected, hypoxic, proximal tubules develop severely compromised energetic function.
Glycine-treated, hypoxic, proximal tubules developed a progressive energetic defect that resulted in failure to restore ATP levels to greater than 10 to 20% of control values during reoxygenation after 60 minutes of hypoxia despite continued cytoprotection by glycine. The defect was not corrected by supplementation with exogenous purines and was not modified by lowering the pH during hypoxia or reoxygenation. In the continued presence of glycine, the failure to restore ATP was associated with impaired recovery of structural changes that developed during hypoxia and, if glycine was withdrawn, lethal membrane damage occurred. The lesion was significantly ameliorated by the presence during hypoxia of two agents known to suppress development of the mitochondrial permeability transition, cyclosporine A and butacaine, which were most effective when used in combination. The data suggest that development of the mitochondrial permeability transition in glycine-protected tubules during hypoxia contributes to continued metabolic and structural impairment and cell death that occur despite glycine replete conditions such as exist frequently during in vivo insults and may be a target for therapeutic maneuvers.
Weinberg
J M
JM
Department of Internal Medicine, University of Michigan, Ann Arbor, USA.
Roeser
N F
NF
Davis
J A
JA
Venkatachalam
M A
MA
D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D062365:Aminobenzoates; D000818:Animals; D002331:Carnitine / Q000494:pharmacology; D002352:Carrier Proteins / Q000032:analysis; D015687:Cell Hypoxia / Q000187:drug effects*; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005998:Glycine / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008840:Microfilament Proteins / Q000032:analysis; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D010590:Phalloidine / Q000032:analysis; D011817:Rabbits; D013997:Time Factors; D062366:para-Aminobenzoates; D013049:Spectrin
D010129:4-Aminobenzoic Acid; D000255:Adenosine Triphosphate; D062365:Aminobenzoates; D002331:Carnitine; D002352:Carrier Proteins; D016572:Cyclosporine; D005998:Glycine; D007770:L-Lactate Dehydrogenase; D008840:Microfilament Proteins; D010590:Phalloidine; D062366:para-Aminobenzoates; D013049:Spectrin; C073325:butacaine