Decline of erythropoietin formation at continuous hypoxia is not due to feedback inhibition

Abstract

human EPO to rats 12 h, 6 h, or immediately before hypoxic exposure to mimic the early increase in EPO levels did not affect endogenous EPO formation during a subsequent hypoxic exposure of 12 h. These results indicate that the early decrease in EPO production at continuous hypoxia is not mediated by a negative feedback control through the effect of EPO on its production sites or target cells. Although the reduction in EPO production rate occurs independent of the amount of EPO produced, the magnitude of the decline appears to be related to the degree of the preceding stimulation. normobaric hypoxia; kinetics; messenger RNA; half-life TO ADAPT RED CELL MASS to oxygen demand of the organism, the glycoprotein hormone erythropoietin (EPO) is produced by the kidneys in inverse correlation with the oxygen content of arterial blood. Following acute hypoxic hypoxia, an increase in renal EPO mRNA has been demonstrated after 1 h (27), and circulating EPO increases within 1.5-2 h (27). Interestingly, it has been demonstrated that EPO levels reach maximal values after 6-24 h in rodents (1,5,15,17, 20,22,26, 31) and within 48 h in humans (1,24) and thereafter decline despite continued hypoxia. This early decrease in EPO levels occurs before red cell mass and therewith blood oxygen content has increased significantly (1,17,20,26).The mechanisms of this early decline have not been clarified but several hypotheses have been developed. Because circulating EPO levels are determined by the production rate and the clearance rate of the hormone, possible alterations in both have to be considered. One concept has early been proposed suggesting that EPO consumption might be increased by activated erythropoietic tissue (31). This has been supported by some clearance studies (21, 25) but others found no difference in EPO clearance rate in animals with hypo-or hyperplastic bone marrow (23) or any change in clearance rate after hypoxia (13). Alternatively, the proliferating erythron might also exert a feedback inhibition on EPO production by mechanisms that would have to be independent of circulating red cell mass. Support for this concept comes from observations suggesting that EPO titers are higher in patients with bone marrow hypoplasia than in comparably anemic patients with active erythropoiesis (9, 28). Other factors that were considered to possibly reduce EPO production independent of erythroid stimulation include a lowered blood oxygen affinity at prolonged hypoxia due to acidosis (8, 20,26, 32) and malnutrition during continuous hypoxic stress. The latter appears, however, not to be the primary mechanism because EPO titers in fed and food-deprived rats were found to increase similarly on repeated hypoxia exposure (18). A further possibility is that EPO production is reduced as a result of a direct feedback inhibition through the hormone itself.The present study in rats was therefore performed to address some of these possibilities and confine the potential mechanisms by which the early decline in EPO levels is brought about. ...

Pharmacodynamic model for chemotherapy-induced anemia in rats

“…Several studies showed that the high EPO production was not sustained but was followed by a rapid decline while animals were still anemic from phlebotomy [33] or under continued hypoxia [34][35][36], suggesting that other regulation processes may be involved. It was revealed that this early decline of EPO was not due to the increase in EPO consumption by the activated progenitor cells since a substantial reduction in EPO mRNA was also observed in kidney along with the EPO decline [34]. Nevertheless, if the stimuli last relatively long, then an addition of a functional adaptation mechanism should be considered [33].…”

“…Eckardt et al [34] conducted a PK study of EPO in rats after i.v. injection of endogenous rat EPO obtained from hypoxic donor animals.…”

Serial immunoreactive erythropoietin levels in autologous blood donors

“…It appears not to be due to a short loop feedback control mechanism of EPO secretion through direct inhibition or via its target cells. 36 It may result from an adaptation to hypoxia at EPO's cellular production sites or from compensatory mechanisms that increase oxygen availability, such as an increase in cardiac output or a decrease in oxygen affinity of hemoglobin. 37 ' 38 Irrespective of the cause of the specific temporal pattern of EPO concentration associated with phlebotomy, the observation that EPO levels and therefore EPO production respond to slight changes in oxygen availability is physiologically important.…”

Age-dependent expression of the erythropoietin gene in rat liver and kidneys.

“…We have therefore addressed the above possibilities by studying the age dependence ofEPO gene expression in rat kidneys and liver under basal conditions and following the exposure to normobaric (hypoxic) hypoxia and carbon monoxide (functional anemia). Both stimuli were applied for a short period of four hours to allow measurements at precisely timed and closely spaced points during the early postnatal phase and to avoid possible confounding effects from adaptive processes which have been observed with more prolonged exposure to hypoxic hypoxia (14,15). To investigate if the duration of stimulation is of central importance in determining organ-specific responsiveness, additional experiments were performed on adult animals studied after three days of repetitive bleeding.…”