Biomedical subjects

J Fandrey

Publications and source records attributed to J Fandrey.

At least 37 records · Page 2Linked to original sources

PubMed1999

Effects of neopterin and 7,8-dihydroneopterin on hypoxia-induced renal erythropoietin production.

Activation of the human cellular immune system is associated with greatly increased formation of the pteridines neopterin and 7,8-dihydroneopterin. It has been postulated that pteridines play a role in the pathogenesis of the anaemia of inflammation. Herein, we studied effects of pteridines on renal function, primarily on the synthesis of erythropoietin (Epo). The experiments were performed with isolated rat kidneys which were perfused hypoxically (pO2 26 mmHg) at constant pressure (100 mmHg) in a serum-free recirculation system for 3 h. The results show that the rate of the production of Epo was significantly lowered when neopterin or 7,8-dihydroneopterin were added to the perfusate. Neopterin (200 microM) also reduced the renal Epo mRNA level. Both pteridines increased renal vascular resistance. 7,8-Dihydroneopterin lowered urine flow and glomerular filtration rate more potently than neopterin. Renal O2 consumption and parameters of exocrine renal function (fractional reabsorption rates of sodium, glucose and water) were not altered by the pteridines, while the glomerular permeability was greatly increased. These results suggest that activated macrophages may not only inhibit the synthesis of Epo by generating cytokines and reactive O2 species but also by the release of pteridines. In vivo, high concentrations of pteridines in renal tissue may aggravate the anaemia of inflammation.

Animals↗

PubMed1999

Effects of pro- and antioxidative compounds on renal production of erythropoietin.

The most important stimulus for the enhanced synthesis of erythropoietin (Epo) is a lowered O2 tension in the tissue. However, the mechanism by which an impaired O2 supply is transduced into appropriate Epo production is still not fully understood. Recently, studies in human hepatoma cells (line HepG2) indicate that reactive O2 species are involved in the signal transduction from the cellular O2 sensor to the Epo gene. To clarify the role of reactive O2 species in the regulation of Epo synthesis in the kidney, the principal Epo-producing organ in vivo, we investigated the influence of potent pro- and antioxidants on Epo production in isolated perfused rat kidneys. Under normoxic conditions, the iron chelator desferrioxamine and the antioxidant vitamin A increased renal Epo production, mimicking hypoxic induction. In contrast, supplementation of the perfusion medium of hypoxically perfused kidneys with the prooxidant compounds H2O2 or pyrogallol caused a significant reduction of Epo synthesis. The inhibition of Epo formation by reactive O2 species could be completely antagonized by desferrioxamine and the hydroxyl radical-(OH*)-scavenger tetramethylthiourea. Vitamin A also antagonized the H2O2-dependent inhibition of hypoxically induced Epo synthesis. Interestingly, the addition of the antioxidant vitamin A to hypoxically perfused kidneys also induced Epo production significantly. Our data strongly support the idea that reactive O2 species, especially H2O2, are part of the signaling chain of the cellular O2-sensing mechanism regulating the renal synthesis of Epo.

Animals↗

PubMed1998

The influence of phenobarbital on cytochromes and reactive oxygen species in erythropoietin producing HepG2 cells.

Light absorption photometry of HepG2 cells treated with phenobarbital for enhancing the content of cytochrome P-450 and the synthesis of erythropoietin revealed an influence on all cytochromes detectable in the wavelength range between 400 and 620 nm. No correlation was found between specific changes of cytochrome P-450 absorption and increased EPO synthesis as proposed earlier by Fandrey et al. (Life Sci. (1990) 47, 127-134). In the present study, however, the increased erythropoietin synthesis could be related to a decreased intracellular hydroxyl radical level described as crucial for the oxygen regulated gene expression (Kietzmann et al., Biochem. J. (1998) 335, 425-432; Porwol et al., Eur. J. Biochem. (1998) 256, 16-23).

Cytochrome P-450 Enzyme System↗

PubMed1998

Erythropoietin mRNA expression in human fetal and neonatal tissue.

Based on animal experiments, a switch of the erythropoietin (EPO) production site from the liver in the fetus to the kidneys in the adult has been postulated. To study the switch in humans, we have quantitated EPO mRNA expression in liver, kidney, spleen, and bone marrow of human fetuses and neonates by means of a competitive polymerase chain reaction (PCR). Tissue samples from 66 routine postmortem examinations were obtained. EPO mRNA was expressed in 97% of the tissue specimen derived from the liver (n = 66) and in 93% of those from the kidneys (17 weeks of gestation until 18 months after birth; n = 59). For the first time the EPO gene was found expressed in vivo in human spleen (96% of 64 samples) and in fetal and neonatal bone marrow (81% of 21 samples). EPO mRNA expression in the kidneys increased significantly beyond 30 weeks of gestation (P < .05). Although there was a slight decrease in EPO mRNA content per g liver tissue towards birth, the liver accounted for about 80% of the total body EPO mRNA. The contribution of the spleen and bone marrow were minor compared with liver and kidneys. Our results indicate that in humans the liver is the primary site of EPO gene expression not only in fetal, but also in neonatal life. A significant increase of renal EPO mRNA expression after 30 weeks of gestation might indicate the beginning switch.

Bone Marrow↗

PubMed1998

The influence of nickel and cobalt on putative members of the oxygen-sensing pathway of erythropoietin-producing HepG2 cells.

Cobalt and nickel stimulate, as does hypoxia, the production of erythropoietin (EPO) in HepG2 cells. Under hypoxic conditions, a decrease in the level of intracellular reactive oxygen species (ROS) is thought to stimulate EPO expression. Cobalt and nickel may interact with the putative oxygen sensor by changing the redox state of the central iron atom of heme proteins, similar to the effects of hypoxia. It was investigated, therefore, whether cobalt and nickel interact with hemeproteins or ROS scavenging systems in the control of intracellular ROS level. Cobalt chloride (100 microM, 24 h) oxidized non respiratory as well respiratory hemeproteins and increased the oxygen consumption. In contrast, nickel chloride (300 microM, 24 h) primarily reduced respiratory hemeproteins and decreased the oxygen consumption. In HepG2 cells treated with CoCl2, iron and cobalt were localized in cytosolic granules close to the cell nucleus and in mitochondria at concentrations up to 12 mM or 41 mM, respectively. Intracellular nickel was not measurable. Three-dimensional reconstruction of confocal laser microscopy images revealed hot spots of hydroxyl radical generation by a Fenton reaction at the sites of cytosolic iron accumulation. The .OH levels decreased in cobalt-treated (to 81%) as well as in nickel-treated (to 67%) HepG2 cells, accompanied by an increase of EPO expression to 167% and 150%, respectively. Our results underline the importance of .OH formed by a Fenton reaction for triggerimg EPO production. Identification of the primary hemeprotein being the oxygen sensor was not possible due to the antagonistic effects of cobalt and nickel on the redox state of detectable hemeproteins.

Carcinoma, Hepatocellular↗

PubMed1998

Manganese augments nitric oxide synthesis in murine astrocytes: a new pathogenetic mechanism in manganism?

Since manganese (Mn2+) is known to be sequestered in glial cells, we investigated possible neurotoxic mechanisms involving astrocytes in vitro. Low concentrations of Mn2+ were toxic only in astrocyte-neuronal cocultures but not in pure astrocyte or neuronal cultures. As a possible mediator of manganese-derived neurotoxicity, we measured the production of nitric oxide in astrocytes. Manganese, but not other transition metals, dose dependently increased iNOS mRNA and protein levels and the release of nitric oxide in activated astrocytes. This effect was specific for astrocytes, since we observed no stimulation in microglial cells. The observations suggest that besides the known inhibition of mitochondrial function the neurotoxic effect of manganese in low concentrations might be mediated by the increased production of nitric oxide in astrocytes.

Animals↗

PubMed1998

Effects of modulators of the production and degradation of hydrogen peroxide on erythropoietin synthesis.

Erythropoietin (Epo) synthesis is suppressed in normoxia and stimulated in hypoxia. To test the hypothesis that the cellular H2O2 level is important in the control of Epo synthesis, we have studied effects of modulators of H2O2 generation and degradation on Epo production in human hepatic cell cultures (hepatoma lines HepG2 and Hep3B). In addition, we measured the activities of antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase) in cultures following hypoxia exposure or H2O2 treatment. The results show that the formation of immunoreactive Epo was stimulated in normoxic cultures by treatment with exogenous catalase thus mimicking the effect of hypoxia (24 h incubation periods). Epo production was also stimulated when scavengers of reactive O2 species (tetramethylthiourea, dihydrorhodamine) were added to the cells. On the other hand, stimulators of H2O2 generation (xanthine oxidase, glucose oxidase, NADH, NADPH) lowered Epo production in hypoxic cultures. Hypoxia exposure decreased superoxide dismutase activity and H2O2 treatment reduced catalase activity thus influencing the endogenous antioxidant defense system. These findings support the concept that reactive O2 species, primarily H2O2, act as messengers in the O2-dependent control of the hepatic production of Epo. Changes in the cellular activities of antioxidant enzymes appear to play only a minor role in this process.

Carcinoma, Hepatocellular↗

PubMed1998

Expression of vascular endothelial growth factor during the development of cardiac hypertrophy in spontaneously hypertensive rats.

Left ventricular hypertrophy (LVH) is often associated with an impaired maximal coronary blood flow and increases the vulnerability of the heart tissue to ischaemia. In this study, the correlation between coronary blood flow and expression of the vascular endothelial growth factor (VEGF) mRNA was investigated. Using both haemodynamic measurements and analysis of mRNA, we have demonstrated that during development of LVH, in spontaneously hypertensive rats (SHR), an impaired maximal coronary flow at 12 weeks of age is associated with low levels of VEGF mRNA. However, in older SHR (32 weeks) with stabilised hypertrophy and a normal maximal coronary flow response, VEGF mRNA levels are increased 3-fold. These results suggest that the mechanism for the impaired flow, observed in some types of cardiac hypertrophy, might involve an inadequate growth of the coronary vessels due to insufficient activation of the VEGF gene.

Animals↗

PubMed1998

Serum erythropoietin concentration in anaemia of visceral leishmaniasis (kala-azar) before and during antimonial therapy.

Serum erythropoietin (Epo) concentrations and variables of red cell and iron status were studied in 27 Sudanese patients who were treated with sodium stibogluconate for visceral leishmaniasis (kala-azar). Blood haemoglobin increased from 6.4 (+/- 1.7 SD) to 9.5 (+/- 1.4) g/dl during treatment. Serum ferritin decreased concomitantly. Serum iron levels were unchanged whereas the total iron binding capacity increased slightly. The pre-treatment serum Epo concentration in relation to the blood haemoglobin concentration was not as high as expected from the one in primary haematological diseases, indicating that there is a relative lack of Epo in anaemic kala-azar patients. Serum Epo further decreased during stibogluconate therapy. The normal dependence of the serum Epo level on the blood haemoglobin concentration was lost during mid-term antimonial treatment, but it recovered thereafter. Cell culture studies with the human hepatoma cells HepG2 showed that stibogluconate (> or = 30 microg/ml) inhibited Epo gene expression. Thus, effective treatment of kala-azar with stibogluconate results in improvement of anaemia, although the drug itself may impair Epo production.

Adult↗

PubMed1998

Tumor necrosis factor-alpha production by human hepatoma cell lines is resistant to drugs that are inhibitory to macrophages.

Little is known about the potential of immunomodulatory agents to lower tumor necrosis factor-alpha (TNF-alpha) synthesis in tissues of nonmonocytic origin. We studied effects of diverse drugs on the formation of immunoreactive TNF-alpha in the human hepatoma cell lines HepG2 and Hep3B, in which TNF-alpha production was induced by treatment (3 h incubation periods) with interleukin-1beta (IL-1beta, 300 pg/ml) or phorbol myristate acetate (PMA, 100 nmol/l). TNF-alpha production in IL-1beta-stimulated or PMA-stimulated hepatocyte cultures was not altered following the addition of dihydrocortisone (< or = 1 microg/ml), dibutyryl-cAMP (db-cAMP, < or = 100 micromol/l), adenosine (< or = 1 mmol/l), thalidomide (< or = 25 microg/ml), or cyclosporine (< or = 300 ng/ml). TNF-alpha production was inhibited by taurolidine (> or = 300 microg/ml), but this inhibition was associated with reduced cell viability. Pentoxifylline (1 mg/ml) did not influence PMA-induced TNF-alpha production, but it augmented IL-1beta-induced TNF-alpha production. Measurements of TNF-alpha mRNA by RT-PCR indicated that pentoxifylline exerted its effect posttranscriptionally. Additional studies with PMA-treated human whole blood cultures confirmed that pentoxifylline, db-cAMP, and adenosine reduced TNF-alpha production by leukocytes. These results provide first evidence to assume cell type-specific effects of immunomodulatory drugs on TFN-alpha synthesis, which may be relevant with respect to their clinical application.

Adjuvants, Immunologic↗

PubMed1997

Suppression of the oxidative burst in murine microglia by nitric oxide.

The effect of nitric oxide (NO) on the oxidative burst was analyzed in purified murine microglial cells in vitro. The generation of reactive oxygen derivatives was monitored with the use of luminol-dependent chemiluminescence. After inducing the endogenous NO production with interleukin 1beta (IL-1beta) and interferon-gamma (IFN-gamma) the superoxide anion release was significantly reduced, which was reversed by the inhibition of the NO synthase. Additionally, chemical NO-releasing compounds reduced the generation of reactive oxygen derivatives rapidly and independently of the pathway used to trigger the oxidative burst. This effect of NO was not mediated via guanylyl cyclase and cGMP, or due to the scavenging of released superoxide anions. This attenuation of superoxide anion generation by NO may limit deleterious effects of the release of reactive oxygen derivatives in tissue inflammation or injury.

Animals↗

PubMed1997

Effects of erythropoietin on endothelin-1 synthesis and the cellular calcium messenger system in vascular endothelial cells.

A rise in blood pressure is the main side effect of erythropoietin (EPO) treatment in patients with renal anemia. The mechanisms, however, by which EPO may cause hypertension are still unclear. We therefore investigated the effects of EPO on endothelin (ET) synthesis and cytosolic free calcium concentration ([Ca2+]i) in vascular endothelial cells. Porcine endothelial cells were isolated from thoracic aorta, pulmonary artery, and vena cava. Studies were performed with cells of the first subculture. ET concentrations were measured radioimmunologically. Changes in [Ca2+]i were determined with the fluorescent probe fura-2. Cytotoxicity was assessed by sodium 3'-[1-(phenyl-amino-carbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)ben zene sulfonic acid hydrate (XTT) assay. ET synthesis was similar in cells of different vascular origins and was time-dependent, reaching approximately 2 pmol ET/mg protein within 12 h of incubation. EPO (12 to 200 U/mL) stimulated ET release time- and dose-dependently by up to 83.2% (P < .01) within 12 h in the absence of fetal calf serum and heparin. EPO induced an immediate significant rise in [Ca2+]i from 58 +/- 12 nmol/L to 495 +/- 85 nmol/L (P < .01) with a subsequent slow return to 257 +/- 3 nmol/L. During 2 h of incubation, the Ca-ionophore A 23187 (10(-8) mol/L) moderately but significantly stimulated endothelial ET synthesis. However, the Ca-channel blocker verapamil, the intracellular Ca-release blocker TMB-8, and nickel, an unspecific calcium channel blocker, had no consistent effects on [Ca2+]i or ET synthesis. The protein kinase C inhibitor H-7 stimulated basal [Ca2+]i and cellular ET synthesis. The tyrosine kinase inhibitor genistein suppressed the EPO-induced rise in [Ca2+]i and cellular ET synthesis. From these data we conclude that EPO may stimulate ET synthesis in vascular endothelial cells by activation of an EPO-receptor and via intracellular signalling mechanisms that comprise tyrosine kinase activation and a rise in [Ca2+]i. Therefore, the systemic hypertensive effects of EPO may be due at least in part to local stimulation of vascular endothelial ET synthesis via calcium mobilization.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1997

Cobalt and desferrioxamine reveal crucial members of the oxygen sensing pathway in HepG2 cells.

Cobalt and desferrioxamine, like hypoxia, stimulate the production of erythropoietin in HepG2 cells. It is believed that cobalt as well as desferrioxamine interact with the central iron atom of heme proteins by changing their redox state similar to hypoxia. A subsequent decrease of the intracellular H2O2 levels under hypoxia was presumed to be the key event for stimulating erythropoietin production. We therefore investigated whether cobalt and desferrioxamine control the intracellular H2O2 levels that regulate gene expression by interacting with hemeproteins. Deconvolution of light absorption spectra revealed respiratory heme proteins such as cytochrome c, b558 and cytochrome aa3, as well as cytochrome b558, which is a nonrespiratory heme protein found in HepG2 cells. Whereas respiratory heme proteins are located in mitochondria, cytochrome b558 similar to the one described for the neutrophil NADPH oxidase can be visualized in the cell membrane of HepG2 cells by immunohistochemistry. Incubation with cobalt (100 microM/24 hr) interacts predominantly with cytochrome b558 and cytochrome b558. The interaction of cobalt with the respiratory chain results in an increased oxygen consumption of HepG2 cells as revealed by PO2 microelectrode measurements. Desferrioxamine (130 microM/24 hr), however has no influence on the cytochromes. In response to an external application of NADH (1 mM), the membrane bound cytochrome b558 produces two times more O2- than to the external NADPH (1 mM) application. Neither desferrioxamine not cobalt has any influence on the NADH stimulated O2- generation. Incubation with cobalt or with desferrioxamine, however, leads to a decrease of the intracellular H2O2 level as revealed by the dihydrorhodamine 123 technique, perhaps causing the well-known enhanced erythropoietin production. The cobalt-induced H2O2 decrease seems to be caused by an increased activity of the glutathion peroxidase that is also induced under hypoxia. Desferrioxamine, however, leads to an apparent H2O2 decrease only because it seems to inhibit the iron catalyzed reaction of H2O2 with dihydrorhodamine 123, hinting at the occurrence of the Fenton reaction in HepG2 cells. Therefore, it must be determined whether or not degradation products of H2O2 by the Fenton reaction suppress erythropoietin production under normoxia.

Cell Line↗

PubMed1997

Cobalt chloride and desferrioxamine antagonize the inhibition of erythropoietin production by reactive oxygen species.

We have recently proposed a H2O2-generating b-type cytochrome as part of the cellular oxygen sensor that controls O2-dependent erythropoietin (Epo) production in the human hepatocellular carcinoma cell line HepG2. H2O2 could act as an intracellular signaling molecule because its production in HepG2 cells is strictly dependent on the pericellular PO2. High cellular levels of H2O2 inhibit hypoxia-induced Epo production while low levels-as under hypoxic conditions-allow full expression of the Epo gene. Since cobalt chloride (CoCl2) and the iron chelator desferrioxamine (DSF) both mimic the hypoxic induction of Epo production we studied the influence of CoCl2 and DSF on the formation and on the action of reactive O2-species with respect to Epo production. Both chemicals reduced the H2O2-dependent 123-dihydrorhodamine fluorescence in HepG2 cells. The inhibition of Epo production by exogenous H2O2 was completely antagonized by DSF. This might indicate that H2O2 exerts its inhibition through a Fenton type reaction. On the other hand, NADPH and pyrogallol which stimulate the production of O2- inhibited Epo production. CoCl2 antagonized their effects. From our results we propose different sites of interaction with the putative signaling chain for DSF and CoCl2. While DSF appears to reduce the action of the H2O2 molecule, CoCl2 might act further upstream through the induction of H2O2-scavenger systems or by interfering with its production.

Cell Line↗

PubMed1997

Effects of antioxidant vitamins on renal and hepatic erythropoietin production.

An important role in O2 sensing has been assigned to microsomal and membrane-bound b-type cytochromes which generate regulatory reactive O2 species (ROS). Recently, ROS have been shown to suppress the in vitro synthesis of erythropoietin (Epo). We investigated the potential of the antioxidant vitamins A, E and C to enhance renal and hepatic Epo production. Renal effects were studied in isolated serum-free perfused rat kidneys. In control experiments without antioxidant vitamins, Epo secretion amounted to 441 +/- 23 mU/g kidney (mean +/- SEM, N = 5) during the three hour period of hypoxic perfusion (arterial pO2 35 mm Hg). Epo secretion significantly increased to 674 +/- 92 mU/g kidney (N = 7) when vitamins A (0.5 microgram/ml), E (0.5 microgram/ml) and C (10 micrograms/ml) in combination were added to the perfusion medium. The effects of the single vitamins were studied in Epo-producing hepatoma cell cultures (lines HepG2 and Hep3B). Vitamin A induced a dose-dependent increase (half-maximal stimulation at 0.2 microgram/ml) in the production of immunoreactive Epo during 24 hours of incubation (such as 680 +/- 51 U Epo/g cell protein in HepG2 cultures with 3 micrograms/ml retinol acetate compared to 261 +/- 15 U/g in untreated controls; N = 4). In contrast, vitamin E (tested from 0.05 to 500 micrograms/ml) and vitamin C (tested from 2 to 200 micrograms/ml) did not increase Epo production in hepatoma cell cultures. Thus, while vitamins E and C may have the potential to protect cells from oxidative damage, vitamin A exerts a specific stimulation of Epo production. Preliminary evidence suggests that this effect of vitamin A involves increased mRNA levels of hypoxia-inducible factor 1 alpha (HIF-1 alpha).

Animals↗

PubMed1997

Perioperative use of recombinant human erythropoietin in patients refusing blood transfusions. Pathophysiological considerations based on 5 cases.

The efficacy of the administration of recombinant human erythropoietin (rHuEPO) in the treatment of anaemia in critically ill surgical patients refusing red cell transfusions requires further documentation. Herein, we report the outcome of 5 consecutive severely anaemic Jehovah's Witness patients (lowest haemoglobin concentration 27 g/1), who were discharged from the hospital in good condition after treatment. RHuEPO (50-280 U/kg body weight) was daily administered to 4 of the patients, who either exhibited preoperative anaemia or developed postoperative anaemia refractory to endogenous EPO probably due to inflammation. RHuEPO treatment was followed by a steep rise in reticulocytes and haemoglobin concentration. The fifth patient, who exhibited no signs of systemic inflammation following emergency hemicolectomy, was also treated with intravenous iron, but not with rHuEPO. His blood haemoglobin concentration rose from 27 g/l to 92 g/l in 3 wk. These observations indicate that the administration of rHuEPO is justified in the management of life-threatening anaemia, although only on a humanitarian basis, because there is no predictor for the possible spontaneous recovery.

Adult↗

PubMed1997

Decreased erythropoietin response in Plasmodium falciparum malaria-associated anaemia.

One of the most serious manifestations of Plasmodium falciparum malaria is anaemia. Its established causes are increased red cell destruction and ineffective erythropoiesis. Since proinflammatory cytokines have been shown to suppress the in vitro synthesis of erythropoietin (Epo), we measured serum immunoreactive Epo in 90 Sudanese patients suffering from malaria. Even in severe cases of anaemia (blood haemoglobin < 80 g/l), serum Epo levels rarely exceeded 300 U/l. For comparison, serum Epo was increased up to 12,000 U/l in a reference group of Caucasian patients with anaemia not associated with infection. Moreover, the slope of the log Epo/haemoglobin regression line was less steep in malarial anaemia. Thus, as documented for other chronic inflammatory disorders, there is a relative lack of Epo in malaria-associated anaemia. Treatment with the antimalarial drug chloroquine may aggravate the defect in Epo production, because chloroquine inhibited Epo synthesis when tested in cell culture.

Adolescent↗

PubMed1997

Erythropoietin gene expression is suppressed after lipopolysaccharide or interleukin-1 beta injections in rats.

Proinflammatory cytokines play an important role in the pathogenesis of anemia in inflammatory diseases. Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) have been reported to inhibit the synthesis of erythropoietin (EPO) in vitro. To evaluate the in vivo significance of this observation, we have investigated effects of the administration of bacterial lipopolysaccharide (LPS) and IL-1 beta on renal EPO production in rats. Measurements by competitive reverse-transcription polymerase chain reaction showed that EPO mRNA levels were significantly reduced in the kidneys of normoxic rats 6 h after the injection of LPS (0.1 or 1 mg/kg). In addition, LPS and IL-1 beta (1 microgram/kg) inhibited the increase in EPO mRNA and plasma EPO levels when administered to rats before hypoxia exposure (8% O2 in the inspiratory gas). Evidence for an inflammatory reaction in the kidneys of LPS-treated rats was provided by measurements of greatly elevated renal TNF-alpha mRNA levels. Furthermore, kidneys isolated from LPS-created rats produced less immunoreactive EPO when perfused hypoxically in vitro for 2 h. Thus mediators of the immune response inhibit renal EPO gene expression in vivo, which is relevant with respect to the impaired synthesis of EPO in inflammatory diseases in humans.

Animals↗