Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration

Heinicke, Katja; Baum, Oliver; Ogunshola, Omolara O.; Vogel, Johannes; Stallmach, Thomas; Wolfer, David P; Keller, Stephan Sylvest; Weber, Klaus; Wagner, Peter D.; Gassmann, Max; Djonov, Valentin

doi:10.1152/ajpregu.00152.2006

Cited by 48 publications

(51 citation statements)

References 52 publications

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“…The transgenic mouse over-expressing EPO (tg6) has been previously described (Heinicke et al, 2006;Katz et al, 2007;Ruschitzka et al, 2000). Female tg6 mice and their wt littermates were used at the age of 3-5 months.…”

Section: Methodsmentioning

confidence: 99%

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

Lifshitz

Prutchi-Sagiv

Avneon

et al. 2009

Molecular Immunology

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Erythropoietin (EPO) is the main hormone that promotes proliferation and differentiation of erythroid progenitor cells via binding to its surface receptor (EPO-R). Recent studies suggest that this hormone may affect also other cell types, besides the red blood cell lineage. We have previously demonstrated that the immune system is a target of EPO; however, the direct target cells of EPO, as well as the molecular mechanisms underlying its role as an immunomodulator, are unknown. Here we present evidence for functional effects of EPO on dendritic cells (DCs), which are known to initiate the immune response. In-vivo experiments in EPO-injected mice and in transgenic mice over-expressing human EPO showed an increased splenic DC population with a higher cell surface expression of CD80 and CD86. Further analysis based on mouse models, showed that DCs derived in-vitro from bone marrow (BM-DCs) express EPO-R mRNA. In-vitro stimulation of these DCs with recombinant human EPO enhanced viability, upregulated CD80, CD86 and MHC class II and augmented the secretion of IL-12. Biochemical analysis of EPO mediated signaling in the BM-DCs showed activation of the AKT, MAPK and NF-kappaB pathways. EPO stimulation of the BM-DCs led to Tyr-phosphorylation of STAT3. The inability to detect EPO mediated activation of STAT5 in the BM-DCs, suggests that in DCs, STAT3 may play a more important role than STAT5 in EPO-R signaling. Taken together, our data support the premise that DCs are direct targets of EPO, thereby providing an insight to the immunomodulatory functions of EPO.

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Section: Methodsmentioning

confidence: 99%

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

Lifshitz

Prutchi-Sagiv

Avneon

et al. 2009

Molecular Immunology

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“…This elevation causes a doubling of their hematocrit from 40 to 80-90%, and up to 25% of the body weight is directed to the blood (Ruschitzka et al 2000, Vogel et al 2003. Expression of human EPO in these mice has been detected in the brain (where it most probably acts locally) as well as in the lung, from where it reaches circulation (Heinicke et al 2006). As experimental models for diabetes and obesity, we employed phosphatase 1B (PTP1B or PTPN1 as listed in the MGI Database) knockout mice (Elchebly et al 1999) associated with resistance to diabetes (PTP1B K/K ), and ob/ob mice susceptible to diabetes and obesity, reviewed in Houseknecht & Portocarrero (1998).…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin treatment leads to reduced blood glucose levels and body mass: insights from murine models

Katz¹,

Stuible²,

Golishevski³

et al. 2010

Journal of Endocrinology

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Erythropoietin (EPO) regulates proliferation and differentiation of erythroid precursor cells into erythrocytes. The last decade has revealed non-renal sites of EPO production and extrahematopoietic expression of the EPO receptor, thus suggesting that EPO has pleiotropic functions. Here, we addressed the interplay between EPO/glucose metabolism/ body weight by employing a panel of relevant experimental murine models. The models focused on situations of increased EPO levels, including EPO-injected C57BL/6 and BALB/c mice, as well as transgenic mice (tg6) constitutively overexpressing human EPO, thus exposed to constantly high EPO serum levels. As experimental models for diabetes and obesity, we employed protein Tyr phosphatase 1B (PTP1B) knockout mice associated with resistance to diabetes (PTP1B K/K ), and ob/ob mice susceptible to diabetes and obesity. The data presented herein demonstrate EPOmediated decrease in blood glucose levels in all mice models tested. Moreover, in the ob/ob mice, we observed EPOmediated attenuation of body weight gain and reduction of hemoglobin A1c. Taken together, our data bear significant clinical implications of EPO treatment in the management of a wide range of metabolic diseases, thus adding an important novel therapeutic potential to this pleiotropic hormone.

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“…The major source of the increased systemic IL-6 levels was identified to be the kidney, liver and spleen. These organs have already been shown to undergo significant degeneration in this mouse model and significantly contribute to reduced life span of the animal (Heinicke et al, 2006;Ogunshola et al, 2006;Ruschitzka et al, 2000;Vogel et al, 2003;Wagner et al, 2001). …”

Section: Discussionmentioning

confidence: 84%

“…We subsequently identified the main source of the systemically increased IL-6 levels as being the kidney, liver and spleen -organs that are known to undergo significant degeneration during the aging of these mice (Fig. 2C, (Heinicke et al, 2006)). Although brain and heart tissue did not express significantly increased levels of IL-6 the systemically increased IL-6 suggested the possibility of increased infiltration of inflammatory cells within many tissues including the brain parenchyma.…”

Section: Inflammatory Mediators and Cytokines Are Elevated In Aged Tgmentioning

confidence: 99%

“…Generation and characterization of this line showed these mice have a hematocrit of 0.8-0.9 after the first 8-9 weeks without increased blood pressure or altered cardiac output as well as reduced exercise performance and a significantly reduced life span of 9-12 months (Heinicke et al, 2006;Ogunshola et al, 2006;Ruschitzka et al, 2000;Vogel et al, 2003;Wagner et al, 2001). Interestingly both NO mediated relaxation and circulating NO levels are markedly elevated leading to increased vasodilation and protection from cardiac complications (Ruschitzka et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Constitutive excessive erythrocytosis causes inflammation and increased vascular permeability in aged mouse brain

Ogunshola¹,

Moransard²,

Gassmann³

2013

Brain Research

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Excessive erythrocytosis results in severely increased blood viscosity that may compromise the vascular endothelium. Using our transgenic mouse model of excessive erythrocytosis we previously showed that despite altered brain endothelial cell morphology and an activated vasculature, brain vascular integrity was largely maintained up to 4-5 months of age. We now present data showing that persistent long-term damage of the vascular wall during the later stages of adulthood (9-10 months) results in a chronic detrimental inflammatory phenotype and increased vessel permeability that likely contributes to the reduced life span of our erythropoietin overexpressing transgenic mouse. In aged transgenic animals inflammatory cells were detected in brain tissue and elevated RNA and protein levels of inflammatory markers such as IL-6 and TNF were observed in both brain tissue and blood plasma. Additionally, increased expression of p53 and other pro-apoptotic markers, as well as decreased Bcl-xL expression in the brain vasculature, indicated ongoing cell death within the vascular compartment. Finally, abnormally elevated vascular permeability in all organs was detected in correlation with decreased expression of the tight junction protein occludin and the adherens junction protein -catenin in brain. Thus chronic erythrocytosis results in sustained activation of inflammatory pathways, vascular dysfunction and bloodbrain barrier disruption.

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Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration

Cited by 48 publications

References 52 publications

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

Erythropoietin treatment leads to reduced blood glucose levels and body mass: insights from murine models

Constitutive excessive erythrocytosis causes inflammation and increased vascular permeability in aged mouse brain

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