Evidence for the De Novo synthesis of erythropoietin in hypoxic rats.

Significant increases in the serum erythropoietin of male rats occur after the end of a brief hypoxic exposure. These increases in the hormone are almost completely abolished when the kidneys are removed after the hypoxic exposure. Injection of puromycin or cycloheximide after the hypoxic exposure significantly decreases the subseauent increases in serum erythropoietin titers, whereas injections of actinomycin D at this time have no significant effect on erythropoietin levels. Injections of actinomycin D before the hypoxic exposure prevent the increase in serum erythropoietin that normally occurs. These findings suggest that a brief period of hypoxia initiates a DNA-dependent RNA synthesis that regulates the de novo ribosomal synthesis of protein(s involved in the biogenesis of erythrOpoietin and that the kidney is essential for these reactions to occur. C ONSIDERABLE EVIDENCE suggests that the level of erythropoietic ctivity in mammals is ultimately determined by the ratio of oxygen supply to oxygen need in the tissues producing erythropoietin. The low level of blood erythropoietin present in normal animals is not generally measurable in the plethoric mouse biological assay. However, within a short time after altering the oxygen supply to an animal, such as an exposure to a simulated altitude, the blood erythropoietin levels are markedly increased and readily detectable in the biological assay. Evidence will be presented (1) that this increase in circulating erythropoietin is the result of de novo protein synthesis and not simply the release of stored hormone, (2) that the synthesis of the hormone, once triggered, continues for some time after termination of the hypoxic conditions, (3) that the initial triggering of the synthesis of the hormone probably Involves a DNA-dependent RNA synthesis, and (4) that the kidney is essential for synthesis of the hormone.