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      Glomerular Localization of Erythropoietin Receptor mRNA and Protein in Neonatal and Mature Mouse Kidney

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          Background/Aims: Erythropoietin (EPO) possesses well-established hematopoietic properties as the primary stimulator of red blood cell formation by binding to its receptor (EPO-R). Recent evidence suggests pathophysiological roles of EPO in several non-hematopoietic tissues including kidney. Our aim was to further clarify the glomerular localization of EPO-R in normal kidney, as well as changes in its expression during glomerulogenesis. Methods:We analyzed EPO-R mRNA and protein expression in neonatal and adult mouse kidney by in situ hybridization and immunohistochemistry. To confirm the precise localization and developmental changes of EPO-R expression in podocytes in mature and developing glomeruli, we examined co-expression with the podocyte markers WT-1 and synaptopodin. Results: In addition to tubular expression as reported recently, EPO-R expression was observed in podocytes as well as endocapillary cells in the glomeruli from adult mice. In newborn kidney, EPO-R mRNA and protein expression was first observed in developing podocytes in S-shaped bodies with expression subsequently increasing in glomeruli at the capillary-loop and maturing stages. Immunoelectron microscopy also demonstrated cytoplasmic expression of EPO-R that was prominent at the basal sides of podocytes in glomeruli at the late capillary-loop and maturing stage. Conclusion: EPO-R is expressed in developing and mature podocytes in mouse kidney, suggesting a possible role for EPO in podocyte biology.

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          Most cited references 15

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          Erythropoietin gene expression in human, monkey and murine brain.

          The haematopoietic growth factor erythropoietin is the primary regulator of mammalian erythropoiesis and is produced by the kidney and the liver in an oxygen-dependent manner. We and others have recently demonstrated erythropoietin gene expression in the rodent brain. In this work, we show that cerebral erythropoietin gene expression is not restricted to rodents but occurs also in the primate brain. Erythropoietin mRNA was detected in biopsies from the human hippocampus, amygdala and temporal cortex and in various brain areas of the monkey Macaca mulatta. Exposure to a low level of oxygen led to elevated erythropoietin mRNA levels in the monkey brain, as did anaemia in the mouse brain. In addition, erythropoietin receptor mRNA was detected in all brain biopsies tested from man, monkey and mouse. Analysis of primary cerebral cells isolated from newborn mice revealed that astrocytes, but not microglia cells, expressed erythropoietin. When incubated at 1% oxygen, astrocytes showed >100-fold time-dependent erythropoietin mRNA accumulation, as measured with the quantitative reverse transcription-polymerase chain reaction. The specificity of hypoxic gene induction in these cells was confirmed by quantitative Northern blot analysis showing hypoxic up-regulation of mRNA encoding the vascular endothelial growth factor, but not of other genes. These findings demonstrate that erythropoietin and its receptor are expressed in the brain of primates as they are in rodents, and that, at least in mice, primary astrocytes are a source of cerebral erythropoietin expression which can be up-regulated by reduced oxygenation.
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            Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion.

            Erythropoietin (EPO) is upregulated by hypoxia and causes proliferation and differentiation of erythroid progenitors in the bone marrow through inhibition of apoptosis. EPO receptors are expressed in many tissues, including the kidney. Here it is shown that a single systemic administration of EPO either preischemia or just before reperfusion prevents ischemia-reperfusion injury in the rat kidney. Specifically, EPO (300 U/kg) reduced glomerular dysfunction and tubular injury (biochemical and histologic assessment) and prevented caspase-3, -8, and -9 activation in vivo and reduced apoptotic cell death. In human (HK-2) proximal tubule epithelial cells, EPO attenuated cell death in response to oxidative stress and serum starvation. EPO reduced DNA fragmentation and prevented caspase-3 activation, with upregulation of Bcl-X(L) and XIAP. The antiapoptotic effects of EPO were dependent on JAK2 signaling and the phosphorylation of Akt by phosphatidylinositol 3-kinase. These findings may have major implications in the treatment of acute renal tubular damage.
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              Tissue distribution of erythropoietin and erythropoietin receptor in the developing human fetus.

              Erythropoietin receptors (Epo-R) have been demonstrated on several nonhematopoietic cell types in animal models and in cell culture. Our objective was to determine the tissue distribution and cellular specificity of erythropoietin (Epo) and its receptor in the developing human fetus. The expression of Epo and Epo-R mRNA was ascertained by RT-PCR for organs ranging in maturity from 5 to 24 weeks postconception. The cellular location of protein immunoreactivity was then determined using specific antiEpo and antiEpo-R antibodies. Antibody specificity was established by Western analysis. mRNA for Epo and Epo-R was found in all organs in the first two trimesters. Immunolocalization of Epo was limited to the liver parenchymal cells, kidney interstitial cells and proximal tubules, neural retina of the eye, and adrenal cortex. As development progressed, immunoreactivity in the kidney became more prominent. In contrast, immunoreactivity for Epo-R was widespread throughout the body, in cell types including endothelial cells, myocardiocytes, macrophages, retinal cells, cells of the adrenal cortex and medulla, as well as in small bowel, spleen, liver, kidney, and lung. The distribution of Epo and its receptor is more widespread in the developing human than was initially postulated. Epo-R is expressed on many cell types during early fetal development, leading us to speculate that Epo acts in concert with somatic growth and development factors during this period. Further investigation is required to understand the nonhematopoietic role of Epo during human development.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                May 2005
                03 March 2005
                : 100
                : 1
                : e21-e29
                Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan
                84109 Nephron Exp Nephrol 2005;100:e21–e29
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 4, References: 25, Pages: 1
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/84109
                Original Paper

                Cardiovascular Medicine, Nephrology

                Erythropoietin receptor, Synaptopodin, Glomerulogenesis, Podocyte


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