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Regulation of Erythropoietin Production

James W. Fisher

10.1002/cphy.cp080251

Source: Supplement 25: Handbook of Physiology, Renal Physiology

Originally published: 1992

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Physicochemical Properties of Erythropoietin
2 Assay and Standardization of Erythropoietin
3 Model for Kidney Production of Erythropoietin
4 Renal Site of Production of Erythropoietin
5 Extrarenal Erythropoietin Production
6 Sites of Action of Erythropoietin
7 Anemia of Renal Insufficiency
8 Erythropoietin and Polycythemia
9 Pharmacological Agents that Influence Erythropoietin Production
10 Pharmacokinetics of Erythropoietin
11 Potential Therapeutic uses of Erythropoietin
12 Summary
Figure 1. Figure 1.

Amino acid sequence of three mammalian erythropoietins. Sequence of mouse (MS) protein with differences from this sequence in human (HU) and monkey (MO) proteins on first and second lines below MS sequence, respectively. Numbering is from NH2 terminals of HU protein. Asterisks, sites of potential N‐linked glycosylation.

From McDonald et al. 184
Figure 2. Figure 2.

Dose–response regression line for International Reference Preparation(1RP)‐erythropoietin in exhypoxic polycythemic mice using modification of bioassay method of Cotes and Bangham 36.

From Rege et al. 244
Figure 3. Figure 3.

Radioimmunoassay dose–response regression lines with purified recombinant human erythropoietin (Ep) and International Reference Preparation‐erythropoietin (1RP‐Ep) used as standards. B, bound fraction with Ep; Bo, zero binding or binding without Ep.

unpublished observations using the method of Mason‐Garcia et al. 180
Figure 4. Figure 4.

Schematic model for renal oxygen sensing and erythropoietin production. Ep, erythropoietin; R, receptor; Gs, G stimulatory; Ac, adenylyl cyclase; ATP, adenosine triphosphate; cAMP, 3′,5′‐ adenosine cyclic monophosphate.
Figure 5. Figure 5.

Inhibitory effects of theophylline (20 and 80 mg/kg/day, I.P.) on the enhancement of radio‐iron incorporation in red cells induced by adenosine (hatched bars, 1,600 nmol/kg/day, I.V.) and 5′‐N′‐ethyl‐carboxamide (NECA; cross‐hatched bars, 100 nmol/kg/day, I.V.) in combination with 4 h hypoxia. Each value represents mean ±; SEM of 7–13 mice. Number of mice is at bottom of each bar. Mean percent 59Fe incorporation in red cells when standard erythropoietin was administered at 200 and 800 mU/mouse in these experiments was 5.48 ±; 0.73 and 25.07 ±; 1.46, respectively. Asterisks indicate groups significantly different from adenosine or NECA alone (P < 0.05). Mean hematocrit values ranged between 60.6% and 63.7%, and hematocrit values were not significantly different in any group.

From Ueno et al. 298
Figure 6. Figure 6.

Temporal pattern of erythropoietin (Ep) titers in plasma (upper panel) and in kidney tissue (lower panel) of rats during continuous hypoxia at 0.42 atm. Each Ep value is mean ±; SEM of several separate plasma (n = 4–5) or kidney (n = 4–7) samples.

From Jelkmann 139
Figure 7. Figure 7.

Effects of indomethacin on serum prostaglandin E (PGE) levels and plasma erythropoietin titers of dogs (n = 6 dogs in each group) after renal artery constriction (RAC) to 30% of normal flow. ESF, erythropoietic stimulating factor. Values are mean ±; 1 SE. Significantly different from RAC + 1 (0.1 > P > 0.05). Asterisk, significantly different from RAC ±; I (P < 0.05).

From Gross et al. 111
Figure 8. Figure 8.

Erythropoietin (Ep) titers in exhypoxic polycythemic mouse (EHPM) assay microsomal fraction of homogenates from kidneys and livers (EHPM/g tissue wet wt), which were flushed free of blood, and in plasma (EHPM/ml) of hypoxia‐exposed rats (6 h at 0.42 atm). Ep was extracted with phosphate buffer in the ratio of 8 ml/g kidney and 1 ml/g liver. Livers contained no significant EHPM. Each bar is mean ±; SE, and number of experiments is noted.

From Jelkmann and Bauer 141
Figure 9. Figure 9.

Indirect immunofluorescence of frozen section of anemic human kidney with antiserum for purified human recombinant erythropoietin. Note strong granular fluorescence of both glomerular epithelial (A) and interstitial (B) cells.

From Kochevar 157
Figure 10. Figure 10.

Dependency of the erythropoietic activity in glomerular primary cultures on culture time and on O2 concentration in incubation atmosphere (open circles, 20% O2; closed circles, 3.5% O2). The erythropoietic activity is expressed as percentage of the maximal number of erythroid clusters (CFU‐E) in the fetal mouse liver cell assay. Culture medium was changed every 2 days, tenfold concentrated, and dialyzed against phosphate‐buffered saline, pH 7.4. Unconditioned medium is erythropoietically active, because it contains insulin, which stimulates growth of CFU‐E.

From Jelkmann et al. 145
Figure 11. Figure 11.

Effect of chronic anemia on liver to kidney switch of erythropoietin (Ep) synthesis in sheep. Each point represents mean of results from 3 separate animals. Shaded area, period when kidneys assume primary role in Ep formation in normal sheep. Percentages derived from actual values obtained by assaying plasma in exhypoxic polycythemic mice. Mean plasma Ep levels (IU/ml) for groups nephrectomized (closed circles) and hepatectomized (open circles), respectively, were day 145: 0.9, 0.1; day 170: 0.85, 0.1; day 180: 0.95, 0.05; day 190: 0.7, <0.05; day 200: 0.05, 0.65; day 210: <0.05, 0.60.

From Zanjani et al. 319
Figure 12. Figure 12.

Model of erythropoiesis describing mechanism of F cell and A cell production from immature and mature erythroid progenitors. Progeny of pluripotent stem cell (CFU‐S) are stochastically committed to erythroid differentiation and form primitive burst‐forming unit‐erythroid (BFU‐E). These progenitors are called BFU‐EFA, because, if stimulated to undergo functional differentiation by high levels of erythropoeitin (Epo), they form colony‐forming unit‐erythroid (CFU‐EFA) and F cells (red cells containing hemoglobins F and A). Factors synthesized by T cells appear necessary to promote interaction of Epo with progenitors. Under normal circumstances at ambient Epo levels, BFU‐EFA undergo process of maturation–differentiation to BFU‐EA, during which their numbers amplify and their hemoglobin program changes to synthesis of hemoglobin A without hemoglobin F. In further stage of amplication, BFU‐EA and A erythrocytes predominate in blood. Very few BFU‐EFA undergo functional differentiation of ambient levels of Epo. Those that do form rare F cells found in normal blood.

From Nathan et al. 211
Figure 13. Figure 13.

Stages of cellular development in production of erythrocytes. Ep, erythropoietin; RBC, red blood cell; ERC, erythropoietin responsive cells; ECP, erythroid‐committed precursors.

From Schofield and Lajtha 267
Figure 14. Figure 14.

Model for mechanism of anemia of renal disease. CFU‐S, stem cell colony‐forming unit; BFU‐E, erythroid burst‐forming unit; CFU‐E, erythroid colony‐forming unit; RBC, red blood cell.

From Fisher, J. W., H. W. Radtke, and A. B. Rege. Mechanism of the anemia of chronic renal failure. In: Current Concepts in Erythropoiesis, edited by C. D. R. Dunn. Copyright 1983. Reprinted by permission of John Wiley & Sons, Ltd
Figure 15. Figure 15.

Relationship between serum erythropoietin concentration and hematocrit level in children with varying degrees of anemia and normal renal function.

From McGonigle et al. 186
Figure 16. Figure 16.

Relationship between serum erythropoietin concentration and hematocrit level in children with renal disease.

From McGonigle et al. 186
Figure 17. Figure 17.

Effects of uremic serum dialysate fractions derived from gel filtration chromatography on erythrocytic colony formation (A–C). Enumeration of fractions (3.3 ml) begins with void volume (Vo). A: effects of Bio‐Gel P‐2 fractions from normal serum dialysate. B: serum dialysate from azotemic patient. C: serum dialysate from azotemic patient preincubated with spermine antiserum. D: radioactivity (cpm) of 1.1 ml fractions when [14C]spermine tetrahydrochloride was added to uremic serum dialysate prior to fractionation. Bars, SEM of three replicates.

From Radtke et al. 241
Figure 18. Figure 18.

Serum creatinine from normal human subjects and patients with chronic renal failure plotted against serum spermidine (r = 0.699, P < 0.001, y = 31.8X‐4.08).

From Saito et al. 261. Reprinted from Kidney International with permission
Figure 19. Figure 19.

Serum creatinine from normal subjects and patients with chronic renal failure plotted against serum putrescine (r = 0.799, P < 0.001, y = 18.5X − 2.55).

From Saito et al. 261. Reprinted from Kidney International with permission
Figure 20. Figure 20.

Time course of erythropoietin (Ep) production in monolayer cell cultures of human renal carcinoma clone (TP 1 clone 21). Each Ep determination represents mean Ep level (radioimmunoassay) in 3 day spent culture media of renal carcinoma clones and reflects amount of Ep produced by clone during past 3 day incubation period. (Unpublished observations.)
Figure 21. Figure 21.

Effects of dibutyryl adenosine 3′,5′‐cyclic monophosphate (dbcAMP) on cell growth, erythropoietin (Ep) production, and dome formation in primary monolayer cultures of human renal carcinoma cells. Renal carcinoma cells grown for 6 days to semiconfluency and for 12 days to confluency were incubated for 6 days in media with and without 0.1 mmol/liter of dbcAMP. Incubation media were assayed for Ep by radioimmunosassay and amount of Ep produced by renal carcinoma cells during 6 day incubation period was calculated after subtracting Ep levels in control unincubated media (6.5 ±; 1.15 mU/ml; n = 3 culture flasks) from those in incubated media. Domes were counted in 9.6 cm2 area after 6 days of incubation. Note significant increase in Ep production and dome formation by confluent cultures of renal carcinoma cells in presence of 0.1 mmol dbcAMP. *P < 0.01 when compared with controls.

From Hagiwara et al. 121
Figure 22. Figure 22.

Mean hourly blood O2 saturation values on perfusates of isolated kidneys perfused with hypoxic blood alone or hypoxic blood containing cobalt. Each point on cobalt curve represents mean of six experiments and on control curve, five experiments. Standard error of mean is shown for each point.

From Fisher and Langston 73
Figure 23. Figure 23.

Hematocrit response in patients with progressive renal failure given erythropoietin three times per week. Four patients received 100 units/kg subcutaneously (open circles), and four patients received 150 units/kg intravenously (solid circles). Results are expressed as means ±; SD.

From Eschbach et al. 57


Figure 1.

Amino acid sequence of three mammalian erythropoietins. Sequence of mouse (MS) protein with differences from this sequence in human (HU) and monkey (MO) proteins on first and second lines below MS sequence, respectively. Numbering is from NH2 terminals of HU protein. Asterisks, sites of potential N‐linked glycosylation.

From McDonald et al. 184


Figure 2.

Dose–response regression line for International Reference Preparation(1RP)‐erythropoietin in exhypoxic polycythemic mice using modification of bioassay method of Cotes and Bangham 36.

From Rege et al. 244


Figure 3.

Radioimmunoassay dose–response regression lines with purified recombinant human erythropoietin (Ep) and International Reference Preparation‐erythropoietin (1RP‐Ep) used as standards. B, bound fraction with Ep; Bo, zero binding or binding without Ep.

unpublished observations using the method of Mason‐Garcia et al. 180


Figure 4.

Schematic model for renal oxygen sensing and erythropoietin production. Ep, erythropoietin; R, receptor; Gs, G stimulatory; Ac, adenylyl cyclase; ATP, adenosine triphosphate; cAMP, 3′,5′‐ adenosine cyclic monophosphate.



Figure 5.

Inhibitory effects of theophylline (20 and 80 mg/kg/day, I.P.) on the enhancement of radio‐iron incorporation in red cells induced by adenosine (hatched bars, 1,600 nmol/kg/day, I.V.) and 5′‐N′‐ethyl‐carboxamide (NECA; cross‐hatched bars, 100 nmol/kg/day, I.V.) in combination with 4 h hypoxia. Each value represents mean ±; SEM of 7–13 mice. Number of mice is at bottom of each bar. Mean percent 59Fe incorporation in red cells when standard erythropoietin was administered at 200 and 800 mU/mouse in these experiments was 5.48 ±; 0.73 and 25.07 ±; 1.46, respectively. Asterisks indicate groups significantly different from adenosine or NECA alone (P < 0.05). Mean hematocrit values ranged between 60.6% and 63.7%, and hematocrit values were not significantly different in any group.

From Ueno et al. 298


Figure 6.

Temporal pattern of erythropoietin (Ep) titers in plasma (upper panel) and in kidney tissue (lower panel) of rats during continuous hypoxia at 0.42 atm. Each Ep value is mean ±; SEM of several separate plasma (n = 4–5) or kidney (n = 4–7) samples.

From Jelkmann 139


Figure 7.

Effects of indomethacin on serum prostaglandin E (PGE) levels and plasma erythropoietin titers of dogs (n = 6 dogs in each group) after renal artery constriction (RAC) to 30% of normal flow. ESF, erythropoietic stimulating factor. Values are mean ±; 1 SE. Significantly different from RAC + 1 (0.1 > P > 0.05). Asterisk, significantly different from RAC ±; I (P < 0.05).

From Gross et al. 111


Figure 8.

Erythropoietin (Ep) titers in exhypoxic polycythemic mouse (EHPM) assay microsomal fraction of homogenates from kidneys and livers (EHPM/g tissue wet wt), which were flushed free of blood, and in plasma (EHPM/ml) of hypoxia‐exposed rats (6 h at 0.42 atm). Ep was extracted with phosphate buffer in the ratio of 8 ml/g kidney and 1 ml/g liver. Livers contained no significant EHPM. Each bar is mean ±; SE, and number of experiments is noted.

From Jelkmann and Bauer 141


Figure 9.

Indirect immunofluorescence of frozen section of anemic human kidney with antiserum for purified human recombinant erythropoietin. Note strong granular fluorescence of both glomerular epithelial (A) and interstitial (B) cells.

From Kochevar 157


Figure 10.

Dependency of the erythropoietic activity in glomerular primary cultures on culture time and on O2 concentration in incubation atmosphere (open circles, 20% O2; closed circles, 3.5% O2). The erythropoietic activity is expressed as percentage of the maximal number of erythroid clusters (CFU‐E) in the fetal mouse liver cell assay. Culture medium was changed every 2 days, tenfold concentrated, and dialyzed against phosphate‐buffered saline, pH 7.4. Unconditioned medium is erythropoietically active, because it contains insulin, which stimulates growth of CFU‐E.

From Jelkmann et al. 145


Figure 11.

Effect of chronic anemia on liver to kidney switch of erythropoietin (Ep) synthesis in sheep. Each point represents mean of results from 3 separate animals. Shaded area, period when kidneys assume primary role in Ep formation in normal sheep. Percentages derived from actual values obtained by assaying plasma in exhypoxic polycythemic mice. Mean plasma Ep levels (IU/ml) for groups nephrectomized (closed circles) and hepatectomized (open circles), respectively, were day 145: 0.9, 0.1; day 170: 0.85, 0.1; day 180: 0.95, 0.05; day 190: 0.7, <0.05; day 200: 0.05, 0.65; day 210: <0.05, 0.60.

From Zanjani et al. 319


Figure 12.

Model of erythropoiesis describing mechanism of F cell and A cell production from immature and mature erythroid progenitors. Progeny of pluripotent stem cell (CFU‐S) are stochastically committed to erythroid differentiation and form primitive burst‐forming unit‐erythroid (BFU‐E). These progenitors are called BFU‐EFA, because, if stimulated to undergo functional differentiation by high levels of erythropoeitin (Epo), they form colony‐forming unit‐erythroid (CFU‐EFA) and F cells (red cells containing hemoglobins F and A). Factors synthesized by T cells appear necessary to promote interaction of Epo with progenitors. Under normal circumstances at ambient Epo levels, BFU‐EFA undergo process of maturation–differentiation to BFU‐EA, during which their numbers amplify and their hemoglobin program changes to synthesis of hemoglobin A without hemoglobin F. In further stage of amplication, BFU‐EA and A erythrocytes predominate in blood. Very few BFU‐EFA undergo functional differentiation of ambient levels of Epo. Those that do form rare F cells found in normal blood.

From Nathan et al. 211


Figure 13.

Stages of cellular development in production of erythrocytes. Ep, erythropoietin; RBC, red blood cell; ERC, erythropoietin responsive cells; ECP, erythroid‐committed precursors.

From Schofield and Lajtha 267


Figure 14.

Model for mechanism of anemia of renal disease. CFU‐S, stem cell colony‐forming unit; BFU‐E, erythroid burst‐forming unit; CFU‐E, erythroid colony‐forming unit; RBC, red blood cell.

From Fisher, J. W., H. W. Radtke, and A. B. Rege. Mechanism of the anemia of chronic renal failure. In: Current Concepts in Erythropoiesis, edited by C. D. R. Dunn. Copyright 1983. Reprinted by permission of John Wiley & Sons, Ltd


Figure 15.

Relationship between serum erythropoietin concentration and hematocrit level in children with varying degrees of anemia and normal renal function.

From McGonigle et al. 186


Figure 16.

Relationship between serum erythropoietin concentration and hematocrit level in children with renal disease.

From McGonigle et al. 186


Figure 17.

Effects of uremic serum dialysate fractions derived from gel filtration chromatography on erythrocytic colony formation (A–C). Enumeration of fractions (3.3 ml) begins with void volume (Vo). A: effects of Bio‐Gel P‐2 fractions from normal serum dialysate. B: serum dialysate from azotemic patient. C: serum dialysate from azotemic patient preincubated with spermine antiserum. D: radioactivity (cpm) of 1.1 ml fractions when [14C]spermine tetrahydrochloride was added to uremic serum dialysate prior to fractionation. Bars, SEM of three replicates.

From Radtke et al. 241


Figure 18.

Serum creatinine from normal human subjects and patients with chronic renal failure plotted against serum spermidine (r = 0.699, P < 0.001, y = 31.8X‐4.08).

From Saito et al. 261. Reprinted from Kidney International with permission


Figure 19.

Serum creatinine from normal subjects and patients with chronic renal failure plotted against serum putrescine (r = 0.799, P < 0.001, y = 18.5X − 2.55).

From Saito et al. 261. Reprinted from Kidney International with permission


Figure 20.

Time course of erythropoietin (Ep) production in monolayer cell cultures of human renal carcinoma clone (TP 1 clone 21). Each Ep determination represents mean Ep level (radioimmunoassay) in 3 day spent culture media of renal carcinoma clones and reflects amount of Ep produced by clone during past 3 day incubation period. (Unpublished observations.)



Figure 21.

Effects of dibutyryl adenosine 3′,5′‐cyclic monophosphate (dbcAMP) on cell growth, erythropoietin (Ep) production, and dome formation in primary monolayer cultures of human renal carcinoma cells. Renal carcinoma cells grown for 6 days to semiconfluency and for 12 days to confluency were incubated for 6 days in media with and without 0.1 mmol/liter of dbcAMP. Incubation media were assayed for Ep by radioimmunosassay and amount of Ep produced by renal carcinoma cells during 6 day incubation period was calculated after subtracting Ep levels in control unincubated media (6.5 ±; 1.15 mU/ml; n = 3 culture flasks) from those in incubated media. Domes were counted in 9.6 cm2 area after 6 days of incubation. Note significant increase in Ep production and dome formation by confluent cultures of renal carcinoma cells in presence of 0.1 mmol dbcAMP. *P < 0.01 when compared with controls.

From Hagiwara et al. 121


Figure 22.

Mean hourly blood O2 saturation values on perfusates of isolated kidneys perfused with hypoxic blood alone or hypoxic blood containing cobalt. Each point on cobalt curve represents mean of six experiments and on control curve, five experiments. Standard error of mean is shown for each point.

From Fisher and Langston 73


Figure 23.

Hematocrit response in patients with progressive renal failure given erythropoietin three times per week. Four patients received 100 units/kg subcutaneously (open circles), and four patients received 150 units/kg intravenously (solid circles). Results are expressed as means ±; SD.

From Eschbach et al. 57
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Article Title: Regulation of Erythropoietin Production
 

How to Cite

James W. Fisher. Regulation of Erythropoietin Production. Compr Physiol 2011, Supplement 25: Handbook of Physiology, Renal Physiology: 2407-2438. First published in print 1992. doi: 10.1002/cphy.cp080251