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Pleiotropic functions of erythropoietin.

Erythropoietin (EPO) produced by the fetal liver and adult kidney is an essential stimulator of erythropoiesis. EPO production is regulated through hypoxic activation of gene transcription and possibly hypoxia-induced stabilization of its mRNA. In the liver of early embryos in which EPO production poorly responds to hypoxia, retinoic acid may be an important stimulator. In this decade, new sites of EPO production have been found: central nervous system and reproductive organs. These tissues have a paracrine and/or autocrine system of EPO, which is independent of the endocrine system (kidney/bone marrow) in adult erythropoiesis. In the central nervous system, astrocytes are the main producers of EPO, while EPO receptor is expressed in neurons. EPO protects neurons from a various types of damage. The uterine EPO is likely involved in the estrogen-dependent angiogenesis of the endometrial layer. The possible functions of EPO in other tissues and tissue-characteristic regulation of EPO production are also discussed in this review.