Control of Erythropoietin Production 1

Abstract

Erythropoietin has been known to be the primary humoral agent which regulates erythropoiesis since the early work in 1906 of Carnot and DeFlandre (1). This hormone was first called “hemopoietine” (1) but has subsequently been named “erythropoietin” (Ep) by Bonsdorff and Jalavisto (2). Reissman's experiments (3), in which one of two parabiotic rats was exposed to an atmosphere of reduced oxygen tension and erythropoietic stimulation was seen in both the hypoxic and nonhypoxic partners, awakened renewed interest in a humoral control of erythropoiesis. Erslev (4) confirmed the Carnot experiments (1) when he injected large quantities of plasma from phlebotomized rabbits into recipient animals and found erythropoietic stimulation. The kidney was established as the primary site of production of erythropoietin with the finding by Jacobson <et al. (5) in 1957 that bilateral nephrectomy abolished the erythropoietic response of rats to bleeding. More direct evidence for the role of the kidney was provided in the reports by Kuratowska <et al. (6) and Fisher and Birdwell (7) in 1961 when these investigators demonstrated that erythropoietin could be produced in the isolated perfused kidney following hypoxemic perfusion of the rabbit kidney (6) and the isolated dog kidney perfused with blood containing cobalt (7). This was confirmed by Reissmann and Nomura (167) and by Pavlovic-Kentera <et al. (221) who demonstrated increased Ep levels in the hypoxemic perfused dog (221) and rabbit (167) kidneys. Fisher and Langston (8) demonstrated later that cobalt and hypoxemic perfusion of the isolated perfused dog kidney produced an apparent synergistic effect by enhancing erythropoietin production in the kidney. The mechanism for the control of kidney production of erythropoietin is not well understood but is postulated to be regulated by the oxygen level in a critical renal sensor cell, and has been the subject of several investigations and reviews (9-17).