While the structure and function of erythropoietin (Epo) are well documented, the mechanisms of the regulation of the renal synthesis of Epo are still poorly understood. Most notably, the localization and function of the O₂-sensitive sensor regulating the renal synthesis of Epo is insufficiently characterized. A body of evidence suggests that extrarenal O₂-sensitive sensors, localized particularly in the brainstem, play an important role in this connection. For example, in the experimental model of the isolated rat kidney the release of Epo during hypoxic perfusion is only slightly affected by changes in the hematocrit, i.e., the O₂-carrying capacity of the perfusion medium. In in-vivo-experiments in rats, decreasing the O₂-supply to the kidney through reduction in renal blood flow (ischemic hypoxia) is very much less effective in increasing Epo production than reducing the hemoglobin concentration (anemic hypoxia).

Furthermore, a high cerebral hydrostatic pressure with a consecutive hypoxia of the brainstem (generated by insufflation of synthetic cerebrospinal fluid into the catheterized cisterna magna of rats) significantly increases plasma Epo levels.

Therefore, during hypoxia cerebral O₂-sensitive sensors release humoral factors triggering the renal synthesis of Epo. Investigations are underway to characterize the structure and function of these ‘Epo-releasing-factors’.