Pleiotrophic functions of erythropoietin and tissue-specific regulation of its expression.

Erythropoietin (Epo) produced by the kidney regulates erythropoiesis, brain EPO prevents neuron death, and uterine Epo stimulates estrogen (E-2)-dependent uterine angiogenesis. To characterize the tissue-specific regulation of Epo gene expression, ovariectomized mice were given E-2 and/or exposed to hypoxia and the temporal patterns of stumuli-induced changes in Epo mRNA levels were examined. Epo mRNA levels in the kidney, cerebrum, and cerebellum were elevated markedly within 4 hr after exposure to hypoxia. While the elevated level of Epo mRNA in the kidney decreased markedly within 8 hr despite continuous hypoxia, the high level in the cerebrum was sustained, indicating that down-regulation operates in the kidney but not in the brain. E-2 transiently induced Epo mRNA in the uterus but not in the kidney, cerebrum and cerebellum. Interestingly, the uterine Epo mRNA was hypoxia-inducible only in the presence of E-2. Thus Epo expression appears to be regulated in a tissue-specific manner, endorsing the tissue-specific functions of Epo.