Abstract

In view of the reported findings that the lysosome-containing, light mitochondrial fraction of the kidney contains a factor which generates erythropoietin, cobalt and hypoxia, both of which are known to stimulate erythropoietin formation, were evaluated for their capacity to alter in vivo and in vitro the membrane integrity of rat kidney lysosomes. Cobalt was administered s.c. to normal rats, and other rats were rendered hypoxic by exposure to a reduced atmospheric pressure in a hypobaric chamber for various time intervals. Lysosome membrane stability in vivo was measured by assessing the effects of cobalt and hypoxia on the osmotic fragility of lysosomes. Cobalt and hypoxia provoked a labilization of lysosomal membranes in vivo as indicated by the discharge of lysosomal marker enzymes. These effects were accompanied by elevated plasma titers of acid phosphatase and β-glucuronidase activities. Cobalt failed to elicit effects in vitro on lysosome membrane integrity. Thus, the lysosome-labilizing action of cobalt can be demonstrated only in vivo, and this action may be a reflection of the capacity of cobalt to produce histotoxic hypoxia since tissue hypoxia leads to marked lysosome disruption. The in vivo data might explain, at least in part, the mechanism of action of cobalt and hypoxia in erythropoietin production.