Hepatic erythropoietin response in cirrhosis

Risør, Louise Madeleine; Fenger, Mogens; Olsen, Niels Vidiendal; Möller, Sören

doi:10.3109/00365513.2015.1137351

Cited by 7 publications

(9 citation statements)

References 14 publications

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“…In fact, hypoxia is capable of connecting a variety of signals. It not only affects the activation of HSCs but also acts on a variety of other cells, such as sinusoidal cells, hepatocytes, adipocytes, and liver-resident macrophages (Kuppfer cells) [ 1 , 22 – 24 ]. Secondly, hypoxia-induced structural changes in hepatic fibrosis aggravate the hypoxic environment, thus, in turn, accelerating its pathologic progression of hepatic fibrosis.…”

Section: Discussionmentioning

confidence: 99%

PPARγ Antagonizes Hypoxia-Induced Activation of Hepatic Stellate Cell through Cross Mediating PI3K/AKT and cGMP/PKG Signaling

Xiang

Liu

et al. 2018

PPAR Research

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Background and Aims Accumulating evidence reveals that PPARγ plays a unique role in the regulation of hepatic fibrosis and hepatic stellate cells (HSCs) activation. This study was aimed at investigating the role of PPARγ in hypoxia-induced hepatic fibrogenesis and its possible mechanism. Methods Rats used for CCl4-induced hepatic fibrosis model were exposed to hypoxia for 8 hours each day. Rats exposed to hypoxia were treated with or without the PPARγ agonist rosiglitazone. Liver sections were stained with HE and Sirius red staining 8 weeks later. HSCs were exposed to hypoxic environment in the presence or absence of rosiglitazone, and expression of PPARγ and two fibrosis markers, α-SMA and desmin, were measured using western blot and immunofluorescence staining. Next, levels of PPARγ, α-SMA, and desmin as well as PKG and cGMP activity were detected using PI3K/AKT and a cGMP activator or inhibitor. Results Hypoxia promoted the induction and progress of hepatic fibrosis and HSCs activation. Meanwhile, rosiglitazone significantly antagonized the effects induced by hypoxia. Signaling by sGC/cGMP/PKG promoted the inhibitory effect of PPARγ on hypoxia-induced activation of HSCs. Moreover, PI3K/AKT signaling or PDE5 blocked the above response of PPARγ. Conclusion sGC/cGMP/PKG and PI3K/AKT signals act on PPARγ synergistically to attenuate hypoxia-induced HSC activation.

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Section: Discussionmentioning

confidence: 99%

PPARγ Antagonizes Hypoxia-Induced Activation of Hepatic Stellate Cell through Cross Mediating PI3K/AKT and cGMP/PKG Signaling

Xiang

Liu

et al. 2018

PPAR Research

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“…In a subset of human cirrhotic liver tissue samples, we see enhanced expression of both, EPO and hEPOΔ3. Although elevated blood EPO concentrations are not generally found in patients with cirrhosis 32, 67 , local hepatic tissue hypoxia occurs in patients with cirrhosis 68 . Thus, enhanced EPO and hEPOΔ3 expression in liver cirrhosis is likely explained by hypoxic mechanisms and the observed parallel enhancement in individual samples implies that EPO and hEPOΔ3 transcript expression are co-regulated in vivo .…”

Section: Discussionmentioning

confidence: 98%

EV-3, an endogenous human erythropoietin isoform with distinct functional relevance

Bonnas

Wüstefeld

Winkler

et al. 2017

Sci Rep

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Generation of multiple mRNAs by alternative splicing is well known in the group of cytokines and has recently been reported for the human erythropoietin (EPO) gene. Here, we focus on the alternatively spliced EPO transcript characterized by deletion of exon 3 (hEPOΔ3). We show co-regulation of EPO and hEPOΔ3 in human diseased tissue. The expression of hEPOΔ3 in various human samples was low under normal conditions, and distinctly increased in pathological states. Concomitant up-regulation of hEPOΔ3 and EPO in response to hypoxic conditions was also observed in HepG2 cell cultures. Using LC-ESI-MS/MS, we provide first evidence for the existence of hEPOΔ3 derived protein EV-3 in human serum from healthy donors. Contrary to EPO, recombinant EV-3 did not promote early erythroid progenitors in cultures of human CD34+ haematopoietic stem cells. Repeated intraperitoneal administration of EV-3 in mice did not affect the haematocrit. Similar to EPO, EV-3 acted anti-apoptotic in rat hippocampal neurons exposed to oxygen-glucose deprivation. Employing the touch-screen paradigm of long-term visual discrimination learning, we obtained first in vivo evidence of beneficial effects of EV-3 on cognition. This is the first report on the presence of a naturally occurring EPO protein isoform in human serum sharing non-erythropoietic functions with EPO.

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“…EPO is a hormone that stimulates the bone marrow to produce red blood cells (RBCs). 43 The main site of EPO production in humans shifts from the liver during fetal development to the kidney after birth. In healthy human adults, renal production of EPO accounts for >90% of circulating EPO.…”

Section: Section 4: Erythropoietin Productionmentioning

confidence: 99%

“…In healthy human adults, renal production of EPO accounts for >90% of circulating EPO. 43 While hepatic synthesis of EPO can increase in states of renal failure, this increase is not sufficient to prevent anemia. 44 Several groups have reported that baboons develop anemia following pig kidney xenotransplantation, which is treated with exogenous EPO.…”

Section: Section 4: Erythropoietin Productionmentioning

confidence: 99%

Physiological aspects of pig kidney xenotransplantation and implications for management following transplant

Hansen‐Estruch

Cooper

Judd

2022

Xenotransplantation

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Successful organ transplantation between species is now possible, using genetic modifications. This article aims to provide a comprehensive overview of the differences and similarities in kidney function between humans, primates, and pigs, in preparation for pig-allograft to human xenotransplantation. The kidney, as the principal defender of body homeostasis, acts as a sensor, effector, and regulator of physiologic feedback systems. Considerations are made for anticipated effects on each system when a pig kidney is placed into a human recipient. Discussion topics include anatomy, global kidney function, sodium and water handling, kidney hormone production and response to circulating hormones, acid-base balance, and calcium and phosphorus handling. Based on available data, pig kidneys are anticipated to be compatible with human physiology, despite a few barriers.

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Hepatic erythropoietin response in cirrhosis

Cited by 7 publications

References 14 publications

PPARγ Antagonizes Hypoxia-Induced Activation of Hepatic Stellate Cell through Cross Mediating PI3K/AKT and cGMP/PKG Signaling

PPARγ Antagonizes Hypoxia-Induced Activation of Hepatic Stellate Cell through Cross Mediating PI3K/AKT and cGMP/PKG Signaling

EV-3, an endogenous human erythropoietin isoform with distinct functional relevance

Physiological aspects of pig kidney xenotransplantation and implications for management following transplant

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