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      Does Angiotensin II Modulate Erythropoietin Production in HepG2 Cells?

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          Background: In humans, infusion of angiotensin II increases erythropoietin (EPO) serum levels in a dose-dependent manner. However, it is not known whether angiotensin II stimulates EPO-producing renal fibroblasts directly via a receptor or by alteration of renal hemodynamics with a consecutive decrease of renal blood flow. The purpose of this study was to investigate EPO secretion and gene expression under direct angiotensin II stimulation in a cell model thereby excluding hemodynamic effects. Methods: In an established EPO-secreting cell line (HepG2), EPO concentrations were measured under various conditions (normoxia and hypoxia) and different angiotensin II concentrations. mRNA levels of EPO were analyzed by LightCycler quantitative PCR after reverse transcription normalized to the housekeeping gene cyclophilin. Results: Angiotensin II did not affect EPO production in any concentration (1 n M or 100 µ M) under conditions of normoxia. Reduced oxygen tension (1% O<sub>2</sub>) led to the expected increase of EPO and EPO gene expression. EPO secretion stimulated by hypoxia is not significantly changed by any concentration of angiotensin II. Conclusion: In summary, this study shows that angiotensin II does not alter EPO production in HepG2 cell culture under normoxic or hypoxic conditions. This might point towards the hypothesis that in vivo renal cortical blood flow and consecutively the decrease of oxygen tension may lead to an increase of EPO secretion.

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          Most cited references 23

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          Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10.

          IL (interleukin)-22 is an IL-10-related cytokine; its main biological activity known thus far is the induction of acute phase reactants in liver and pancreas. IL-22 signals through a receptor that is composed of two chains from the class II cytokine receptor family: IL-22R (also called ZcytoR11/CRF2-9) and IL-10Rbeta (CRF2-4), which is also involved in IL-10 signaling. In this report, we analyzed the signal transduction pathways activated in response to IL-22 in a rat hepatoma cell line, H4IIE. We found that IL-22 induces activation of JAK1 and Tyk2 but not JAK2, as well as phosphorylation of STAT1, STAT3, and STAT5 on tyrosine residues, extending the similarities between IL-22 and IL-10. However our results unraveled some differences between IL-22 and IL-10 signaling. Using antibodies specific for the phosphorylated form of MEK1/2, ERK1/2, p90RSK, JNK, and p38 kinase, we showed that IL-22 activates the three major MAPK pathways. IL-22 also induced serine phosphorylation of STAT3 on Ser(727). This effect, which is not shared with IL-10, was only marginally affected by MEK1/2 inhibitors, indicating that other pathways might be involved. Finally, by overexpressing a STAT3 S727A mutant, we showed that serine phosphorylation is required to achieve maximum transactivation of a STAT responsive promoter upon IL-22 stimulation.
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            Evidence of tubular hypoxia in the early phase in the remnant kidney model.

            The remnant kidney model is a mainstay in the study of progressive renal disease. The earliest changes in this model result from glomerular hemodynamic alterations. Given that progressive renal disease is the result of subsequent interstitial damage initiated by undetermined pathogenic factors, the authors investigated the role of hypoxia as a pathogenic factor in tubulointerstitial damage after renal ablation in rats. Cortical tissue hypoxia in the early phase (4 and 7 d) in remnant kidney rats, sham-operated rats, and animals treated with the angiotensin II receptor blocker (ARB) olmesartan (10 mg/kg per d) was assessed by uptake of a hypoxic probe, pimonidazole, expression of HIF-1alpha, and by increased transcription of hypoxia-responsive genes. Physiologic perfusion status of the postglomerular peritubular capillary network was evaluated by lectin perfusion and Hoechst 33342 diffusion techniques. Results showed that the number of hypoxic tubules was markedly increased 4 and 7 d after nephron loss. These findings antedated any histologic evidence of tubulointerstitial damage. The hypoxic state persisted until interstitial damage developed. These results were confirmed using HIF-1alpha immunoprecipitation and increase of hypoxia-responsive genes. Pathologic studies of the vasculature demonstrated significant functional changes that generated a hypoxic milieu. ARB treatment prevented vascular changes and ameliorated tubular hypoxia. These results suggest that the initial tubulointerstitial hypoxia in remnant kidney model plays a pathogenic role in the subsequent development of tubulointerstitial injury. The initial hypoxia in this model was dependent on activation of the renin-angiotensin system and hemodynamic alterations after nephron loss.
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              Isolation and characterization of genomic and cDNA clones of human erythropoietin


                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                December 2004
                22 December 2004
                : 98
                : 4
                : e124-e131
                aAbteilung Pharmakologie und Experimentelle Therapie, bAbteilung Klinische Pharmakologie, Institut für Pharmakologie und Toxikologie, Universitätsklinikum Tübingen, Tübingen, Germany
                81556 Nephron Exp Nephrol 2004;98:e124–e131
                © 2004 S. Karger AG, Basel

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                Page count
                Figures: 10, References: 36, Pages: 1
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/81556
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