SP313LIVER IRON IS A MAJOR REGULATOR OF HEPCIDIN GENE EXPRESSION VIA BMP/SMAD PATHWAY IN A RAT MODEL OF CHRONIC RENAL FAILURE UNDER TREATMENT WITH HIGH rHuEPO DOSES

Abstract

Introduction and Aims: Hepcidin is the major central regulator of iron metabolism, controlling iron absorption and mobilization. Considering its interaction with several factors that are altered in chronic kidney disease (CKD), particularly in hyporesponsive CKD patients under therapy with high recombinant human erythropoietin (rHuEPO) doses, we aimed to study the impact of increasing rHuEPO doses on the regulation of iron-hepcidin metabolism. Methods: Male Wistar rats, 12 weeks old, were divided in 6 groups: CRF (induced by a two-stage 5/6 nephrectomy), CRF-rHuEPO treated (100, 200, 400 and 600IU/Kg body weight/week) during 3 weeks and Sham-operated (surgery without kidney mass reduction). Hematological and iron data were evaluated, as well as, the expression of several genes involving iron metabolism and the quantification of some proteins by western blot. Mann-Whitney test was used to evaluate differences between groups. Results: We found that the rHuEPO stimulus triggers a first wave to achieve correction of anemia, by inhibiting hepcidin synthesis, favoring erythropoiesis and iron absorption; this continuous enhanced iron absorption lead to iron overload, as showed by the hepatic iron deposits found in rats treated with higher rHuEPO dose that seems to trigger the up-regulation of hepcidin synthesis through the activation of the BMP6/SMAD pathway. Conclusions: Our data suggests that liver iron overload is an important stimuli for hepcidin synthesis, stronger than the inhibitory effect of high rHuEPO doses; moreover, our findings raise the hypothesis that when high inflammation (triggering hepcidin expression) is associated with increased iron stores in hemodialysis patients, hepcidin expression is also up-regulated via BMP6, enhancing hepcidin synthesis, leading, therefore, to worsening of anemia and, eventually, to a hyporesponse/resistance to rHuEPO therapy.

Curcumin attenuates erythropoiesis in recombinant human erythropoietin-induced polycythemia in rats

“…In agreement with this result, several studies reported that recombinant human EPO treatment reduced hepcidin secretion. [17,18] The current finding is explained by understanding the methods of hepcidin regulation including plasma iron concentrations, body iron stores, infection and inflammation, and erythropoiesis. [19] The observed decrease in serum iron and ferritin concentrations with combined treatment of EPO and curcumin may suppress hepcidin in a classical endocrine feedback system in which hepcidin production is stimulated by plasma iron and iron stores.…”

Role of Hepcidins from Black Rockfish (Sebastes schlegelii) in Iron-Metabolic Function and Bacterial Defense

“…The peptide was first identified in 2000 as a human liver-expressed antimicrobial protein and was known as LEAP-1. It is also called hepcidin, because it is extracted from liver tissue and has antibacterial properties [28]. Hepcidin is abundant in cysteine and is also present in human urine.…”

A comprehensive validation of HBV-related acute-on-chronic liver failure models to assist decision-making in targeted therapeutics

“…After reviewing the titles and abstracts, 4698 and 35 studies were excluded, respectively. Among the remaining 19 full-text articles, seven articles 16 24 25 26 27 28 29 were excluded for the absence of relevant indicators or because they contained explicit mathematical expressions in their models. Twelve models were eventually included in our study: eight were in the MELD-based system 8 9 10 11 12 13 14 15 , two were in the CTP-based system 17 18 and two were in the LRM-based system 19 20 .…”