Co-administration of erythropoietin and iron complex improves late-phase liver regeneration

Abstract

Erythropoietin and iron have individually shown beneficial effects on early-phase liver regeneration following partial hepatectomy (PHx); however, there are limited data on the combined effect on late-phase liver regeneration after PHx. Here we examined combined effects of recombinant human erythropoietin (rhEPO, 3,000 IU/kg) and iron isomaltoside (IIM, 40 mg/kg) on late-phase liver regeneration following PHx and investigated the possible underlying mechanism. Rats administrated with rhEPO showed significantly higher liver mass restoration, interleukin-6 (IL-6, a hepatocyte mitogen) levels, and Ki-67-positive hepatocytes on day 7 after PHx than saline-treated controls. These beneficial effects were further enhanced on days 7 and 14 by co-treatment with IIM. This combination also significantly improved liver function indices, such as increased albumin production and decreased bilirubin levels, but did not alter serum levels of toxic parameters, such as aspartate transaminase and alanine transaminase. This study demonstrates that the combination of rhEPO and IIM synergistically improves late-phase liver regeneration and function after PHx, probably by promoting IL-6-mediated hepatocyte proliferation without adverse effects. Thus, this combination treatment can be a potential therapeutic strategy for patients undergoing resection for hepatic malignancies.

Selective HIF stabilization alleviates hepatocellular steatosis and ballooning in a rodent model of 70% liver resection

“…Roxadustat has been indeed developed to raise the levels of erythropoietin and, upon roxadustat administration, we registered a blood cell response. Moreover, erythropoietin per se exerts an influence on liver regeneration and metabolism, by inducing hepatic proliferation and decreasing lipid accumulation in the liver [54,55]. Then we additionally measured the plasma levels of erythropoietin to investigate whether our findings could be partly explained by a raise in erythropoietin release but the results did not confirm this hypothesis (Supplemental Information 6).…”

Clinical Factors Affecting the Rate of Liver Regeneration in Living Donors after Right Hepatectomy

“…Increased liver regeneration by stimulation of erythropoiesis is related to increments of Ki-67 proliferation, hepatocyte growth factor (HGF), IL-6, vascular endothelial growth factor (VEGF), and IL-6 [16]. Perioperative erythropoietin has been suggested to stimulate liver regeneration after hepatectomy [17]. Therefore, this should be considered in living donors with small RLVs to promote postoperative liver regeneration.…”

Dual Switch Mechanism of Erythropoietin as an Antiapoptotic and Pro-Angiogenic Determinant in the Retina

“…Neurodegenerative diseases of the retina that include AMD and DR under oxidative stress are initiated from uncontrolled apoptosis and angiogenesis, especially in the aged population worldwide. Many risk factors and biomarkers of these retinal diseases have been reported; however, early molecular mechanisms of the disease development through EPO signaling are elusive. − Multiple factors of retinal disorders are involved in the occurrence, including aging, genetic predispositions, DNA methylation, nutrition, oxygen tension, intense/prolonged light, and diabetic conditions. Key characteristics of the diseases include the compromised structural integrity of microvasculatures, overproduction of reactive oxygen/nitrogen species (ROS/RNS), mitochondrial disruption, and uncontrolled retinal cell death.…”