GLYCINE-PROTECTED, HYPOXIC, PROXIMAL TUBULES DEVELOP SEVERELY COMPROMISED ENERGETIC FUNCTION

Glycine-treated, hypoxic, proximal tubules developed a progressive ene rgetic defect that resulted in failure to restore ATP levels to greate r than 10 to 20% of control values during reoxygenation after 60 minut es of hypoxia despite continued cytoprotection by glycine. The defect was not corrected by supplementation with exogenous purines and was no t modified by lowering the pH during hypoxia or reoxygenation. In the continued presence of glycine, the failure to restore ATP was associat ed with impaired recovery of structural changes that developed during hypoxia and, if glycine was withdrawn, lethal membrane damage occurred .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 hypo xia of two agents known to suppress development of the mitochondrial p ermeability 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 tubu les during hypoxia contributes to continued metabolic and structural i mpairment and cell death that occur despite glycine replete conditions such as exist frequently during in vivo insults and may be a target f or therapeutic maneuvers.