Where is epo produced in the body

Too little erythropoietin could be due to anaemia low red blood cells , especially anaemia due to kidney disease. Increased levels of erythropoietin might be due to a condition called polycythaemia too many red blood cells or it could be evidence of a kidney tumour.

Raised levels of Erythropoietin in athletes indicate erythropoietin abuse doping. EPO doping can boost the number of red blood cells and there by increased availability of oxygen to the muscles. This can help the athlete with increased performance ability and endurance. Blood doping is illegal especially in professional sports.

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Human body. Home Hormones Erythropoietin. Erythropoietin Erythropoietin is a hormone, produced mainly in the kidneys, which stimulates the production and maintenance of red blood cells. Alternative names for erythropoietin Erythropoietin is commonly referred to as EPO. What is erythropoietin? Anemia can result from a broad range of problems, for example from hemorrhage, destruction of red cells due to autoimmunity, or interference with cell production associated with cancer chemotherapy.

As depicted below, anemia leads to hypoxia within the kidney, which triggers additional interstitial cells there to start secreting erythropoietin. Increased secretion of erythropoietin enhances and accelerates the production of new red blood cells from their progenitors. In addition to its effect on red blood cell production in the bone marrow, erythropoietin has been implicated in a number of other cellular effects in vasculature, heart, and nervous system.

The importance of these other influences is poorly understood. Erythropoietin is necessary for life in vertebrates. Mice that are homozygous for deletions of the erythropoietin gene die early in gestation from severe anemia. A common cause of erythropoietin deficiency is chronic kidney disease. When the kidneys are damaged, their ability to produce erythropoietin is compromised and anemia ensues. Interestingly, we have observed REPs around the peritubular capillaries, but not in the regions surrounding the larger vessels Figure 1.

Figure 1. REPs are peri-capillary CDpositive fibroblast-like cells. The nuclei are stained by DAPI blue.

DAPI blue is used for nuclear staining in the merged image. Abbreviations: A, artery; V, vein. The balance between oxygen supply and demand precisely controls renal Epo production. A salient physiological study using isolated rat kidneys with hypoxic perfusate shows that renal Epo secretion is regulated by tissue oxygen tension Pagel et al. Distant organs, such as skin have been found to participate in regulation of renal Epo synthesis through sensing a hypoxic atmosphere Boutin et al.

Recently, Dimke et al. In this mouse model, the kidney has scarce vascularization, resulting in renal hypoxia, increased Epo secretion, and severe polycythemia Dimke et al. Figure 2. Understanding of the Epo gene regulation has been advanced by the discovery of Epo-producing hepatoma cell lines Hep3B and HepG2 Goldberg et al. In order to understand renal Epo gene regulation, transgenic mouse lines with different regulatory regions have been generated.

However, this enhancer is dispensable for renal Epo gene expression, indicating that other cis -elements direct renal Epo production Figure 3. Figure 3. Overview of Epo gene transcriptional regulation. The functional HRE for hepatic Epo gene expression EpoHE is in the proximal downstream region of the transcription end site, whereas a kidney enhancer has been suggested to be located in a region far upstream of the transcription start site.

One of the important lingering questions about Epo gene regulation is the location and characteristics of the regulatory regions for renal Epo gene expression. However, the GATA box is turned out to be indispensable for repressing ectopic Epo gene expression in epithelial lineage cells, including distal tubular cells, bronchial epithelial cells, and cholangiocytes.

Of the transcription factors interacting with these Epo gene regulatory regions, HIFs play the central role in hypoxia-inducible Epo gene expression Haase, ; Suzuki, Table 1. Summary of gene targeting studies of hypoxia-related factors on renal Epo gene regulation. The asparaginyl hydroxylation is more resistant to suppression by hypoxia than the prolyl hydroxylation Tian et al.

FIHdependent hydroxylation is more prone to be inhibited by oxidative stresses than by hypoxic stresses Masson et al. Consistent with these findings, the systemic knockout of FIH-1 does not result in defects in the Epo gene regulation directly Table 1 Zhang et al. All chronic nephropathies progress with tubular atrophy and interstitial fibrosis along with the relative loss of Epo production Quaggin and Kapus, While fibrosis is an essential biological process for repairing tissue injuries, uncontrolled and persistent injuries lead to sustained fibrogenesis, followed by destruction of tissue architecture and organ failure Quaggin and Kapus, ; Friedman et al.

Therefore, the identification of therapeutics controlling the pathological fibrogenic response would be beneficial for many devastating diseases, such as chronic kidney disease CKD , cirrhosis, and pulmonary fibrosis Friedman et al. Since a strong correlation between tubulo-interstitial injury and decreased glomerular filtration rate was first described, many researchers have sought the origin of scar-forming cells, i.

Using genetic lineage tracing, various cellular sources have been postulated as the origins of myofibroblasts, including pericytes, resident fibroblasts, tubular cells, endothelial cells, fibrocytes, and bone marrow-derived cells, but exact contributions of the sources to renal fibrosis still remain under debate summarized in Table 2 Quaggin and Kapus, ; Mack and Yanagita, A possible direct link between the loss of Epo production and progression of fibrosis was first proposed in Maxwell et al.

Maxwell et al. Interestingly, tamoxifen, a selective estrogen receptor modulator, is found to improve the Epo-producing ability of myofibroblasts Asada et al. To better understand the contribution of REPs to renal fibrosis and the link between fibrosis and anemia, ISAM have been utilized as the most efficient reporter mouse model for the Epo-producing ability.

These results indicate that the renal fibrogenic milieu strongly represses Epo gene transcription in REPs during their myofibroblast transformation process Souma et al. Consistent with the finding that renal myofibroblasts contribute to the inflammatory milieu, damage-associated molecular patterns DAMPs induce IL-6 and MCP1 productions in myofibroblasts Campanholle et al. Additionally, the loss of local Epo production might have deteriorating effects on fibrogenesis and inflammation in the kidneys, because cytoprotective function of Epo beyond erythropoiesis has been predicted Noguchi et al.

Figure 4. Myofibroblast transformation of REPs. Blue: DAPI for nuclear staining. EpoGFP protein expression does not reflect ongoing Epo gene transcription due to its longer half-life. Interestingly, the product of the hemoglobin Hb concentration times the Epo concentration in the peripheral blood of patients with diabetic nephropathy correlates well with the stages of diabetic nephropathy and predicts future chronic renal failure in overt diabetic nephropathy Inomata et al.

Although confirmation of this argument waits for larger studies, we surmise that Epo would be a good biomarker to estimate the severity of interstitial injury and to predict the prognosis of damaged kidneys based on the short half-life 4—8 h of Epo Jelkmann, One aspect that makes the determination of the origins of myofibroblasts difficult is the complexity regarding the identity of the interstitial cells, i.

It has been shown that FoxD1-tagged pericytes are the major source of renal myofibroblasts Humphreys et al.

As mentioned above, we found that REPs are the major source of renal myofibroblasts through EpoCre-based functional lineage tracing Souma et al. Recently, Kramann et al. Some clinical and experimental reports have shown that renal structural damage, including fibrosis, is reversible Zeisberg et al.

Furthermore, dexamethasone facilitates this reversion, possibly through enhancing the resolution of inflammation in injured kidneys Souma et al. These results indicate that REPs possess plasticity in response to environmental cues. Consistent with this observation, hepatic myofibroblasts can revert to their normal cellular character hepatic stellate cells during the regression of fibrosis Kisseleva et al. Figure 5. The cellular plasticity of REPs governs both fibrosis and anemia. A Schematic diagram of the reversible UUO model.

The left ureter is obstructed by a vascular clip for 2 days and then re-opened afterwards. C Schematic summary showing the plasticity of REPs. After the resolution of environmental cues, MF-REPs revert to their original and physiological Epo-producing phenotype.

A genome-wide transcriptome analysis of sham-treated kidneys, obstructed kidneys, and recovering kidneys indicates that the atherosclerotic and acute phase response signals are the top two up-regulated pathways and that valine, leucine, and isoleucine degradation and fatty acid metabolisms are the top two down-regulated pathways Souma et al.

Recent transcriptome analyses using kidney samples from human CKD patients reveals that the gene expressions of fatty acid metabolism are decreased and inflammatory signaling is increased in kidney diseases Kang et al.

Based on the fact that metabolic intermediates play an important role in gene regulation, it is of great interest to determine whether deranged fatty acid metabolism would affect Epo production and whether correcting the metabolism, e. Uremic toxins are a group of compounds that are normally excreted by healthy kidneys, but accumulate upon kidney injuries.

These results further emphasize the importance of correcting the unbalanced microenvironment in injured kidneys. However, fewer efforts have been made to decipher the nexus of environmental cues by quantifying the contribution of each cell type to the fibrogenic cues.

Epigenetic alterations, including DNA methylation, play an important role in cellular transformation. Interestingly, the Epo gene locus is highly methylated in cell lines lacking Epo-producing abilities, indicating the importance of DNA methylation for the epigenetic silencing of Epo gene expression Yin and Blanchard, Thus, one would be easy to surmise that the sustained activation of inflammatory and fibrogenic signaling may alter the epigenetic code of REPs and limit the potential of reversing MF-REPs to their original state.

Kidney injuries and subsequent fibrosis disrupt oxygen delivery through vascular rarefactions and excessive extracellular matrix accumulation. Increased oxygen demands also cause kidney cells to be vulnerable to hypoxia. Renal anemia further compromises the delivery of oxygen, and the anemic hypoxia has been suggested to promote kidney diseases Nangaku, Because HIFs are the major regulators of hypoxic adaptation, augmenting HIF signaling has been attempted to treat kidney diseases Miyata et al.

Adequacy of hypoxia signaling upon kidney injuries has been questioned recently. Furthermore, the successful augmentation of Epo production in diseased kidneys by PHD inhibitors implies that the primary cause of Epo insufficiency is the inappropriately high PHD activity in diseased kidneys, despite a severely hypoxic milieu Bernhardt et al.

Collectively, we posit that the response to hypoxia is impaired or insufficient upon kidney injury through inappropriately high PHD activity Souma et al. Epo production is inappropriately repressed despite the presence of severe hypoxia in injured kidneys. Consistent with this observation, inflammatory cytokines elicited in damaged kidneys repress the Epo-producing ability, emphasizing the important effect of sterile inflammation on repressing the Epo-producing ability of REPs Souma et al.

We propose that identifying signals that restore physiological characteristics of REPs in fibrotic kidneys will open a new avenue for treating CKD. To accomplish this goal, several barriers must be overcome. One of the highest barriers is the difficulty in handling REPs. To screen candidate pathway to treat CKD, a good readout that reflects both diseased and recovered states of kidneys is necessary. However, these markers are not perfect for testing whether cells regain their original character upon treatment.

The Epo-producing ability is the important physiological feature of renal fibroblast-like cells, and its loss is the hallmark of renal myofibroblasts. Thus, developing a methodology to culture REPs ex vivo and to monitor their Epo-producing ability by reporter genes would provide an opportunity to perform high-throughput screening to identify novel target signals to restore MF-REPs to normal REPs.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors thank Dr. Masahiro Nezu for critically reading the early manuscript. Asada, N. Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice.

Bechtel, W. Methylation determines fibroblast activation and fibrogenesis in the kidney. Bernhardt, W. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD.

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