The relation between Lead (Pb) and iron (Fe) becomes increasingly concerned because they are both divalent metals that are absorbed by the same intestinal mechanism, and Pb exposure and Fe deficiency in the developmental brain, as well as Fe overload in the aged brain, can cause cognitive deficits. However, the interaction between Pb exposure and Fe status in the brain has not been established. Therefore, in the current study, we examined the effects of maternal ingestion of Pb in drinking water during gestation and lactation on the Fe status and the expression of divalent metal transporter 1 (DMT1) and ferroportin 1 (FP1) in the brain of offspring. The offspring were followed through old age, with measurements taken at postnatal week 3, 41 and 70. Pb exposure increases the Fe content in the old-aged rats' brain, Which might be not subjected to DMT1 mediating, but may be associated with the decrease expression of FP1. Furthermore, the effect of Pb on FP1 expression is regulated at transcriptional and posttranscriptional levels. The perturbation in Fe homeostasis may contribute to the neurotoxicology consequences induced by Pb exposure, and FP1 may play a role in Pb-induced Fe cumulation in the brain.
Ferroportin exports iron into plasma from absorptive enterocytes, erythrophagocytosing macrophages, and hepatic stores. The hormone hepcidin controls cellular iron export and plasma iron concentrations by binding to ferroportin and causing its internalization and degradation. We explored the mechanism of hepcidin-induced endocytosis of ferroportin, the key molecular event in systemic iron homeostasis. Hepcidin binding caused rapid ubiquitination of ferroportin in cell lines overexpressing ferroportin and in murine bone marrow-derived macrophages. No hepcidin-dependent ubiquitination was observed in C326S ferroportin mutant which does not bind hepcidin. Substitutions of lysines between residues 229 and 269 in the third cytoplasmic loop of ferroportin prevented hepcidin-dependent ubiquitination and endocytosis of ferroportin, and promoted cellular iron export even in the presence of hepcidin. The human ferroportin mutation K240E, previously associated with clinical iron overload, caused hepcidin resistance in vitro by interfering with ferroportin ubiquitination. Our study demonstrates that ubiquitination is the functionally relevant signal for hepcidin-induced ferroportin endocytosis.
Aims: Free iron plays an important role in the pathogenesis of acute kidney injury (AKI) via the formation of hydroxyl radicals. Systemic iron homeostasis is controlled by the hemojuvelin-hepcidin-ferroportin axis in the liver, but less is known about this role in AKI. Results: By proteomics, we identified a 42 kDa soluble hemojuvelin (sHJV), processed by furin protease from membrane-bound hemojuvelin (mHJV), in the urine during AKI after cardiac surgery. Biopsies from human and mouse specimens with AKI confirm that HJV is extensively increased in renal tubules. Iron overload enhanced the expression of hemojuvelin-hepcidin signaling pathway. The furin inhibitor decreases furin mediated proteolytic cleavage of mHJV into sHJV and augments the mHJV/sHJV ratio after iron overload with hypoxia condition. The furin inhibitor could reduce renal tubule apoptosis, stabilize hypoxic induced factor-1 (HIF-1), prevent the accumulation of iron in the kidney and further ameliorate ischemic-reperfusion injury. mHJV is associated with decreasing total kidney iron, secreting hepcidin, and promoting the degradation of ferroportin at AKI, whereas sHJV does the opposite. Innovation: This study suggests the ratio of mHJV/sHJV affects the iron deposition during acute kidney injury and sHJV could be an early biomarker of AKI. Conclusion: Our findings link endogenous HJV inextricably with renal iron homeostasis for the first time, add new significance to early predict AKI, and identify novel therapeutic targets to reduce the severity of AKI using the furin inhibitor.
BACKGROUND: Growth differentiation factor 15 (GDF15), a divergent TGFβ superfamily, has recently been implicated in the modulation of iron homeostasis, acting as an upstream negative regulator of hepcidin, the key iron regulatory hormone produced primarily by hepatocytes. However, little is known about possible roles that GDF15 might play in the regulation of iron homeostasis and development of hyperferritinemia in children with hemophagocytic lymphohistiocytosis (HLH). PROCEDURES: We compared serum GDF15 level and mRNA expressions of GDF15 and key molecules of iron metabolism, and made correlations between their expressions in children with HLH and control children. RESULTS: Serum GDF15 level was remarkably higher in HLH group than that in controls, with median serum concentration of 1,700 and 260 pg/ml, respectively (P < 0.001). In addition, GDF15 mRNA was significantly upregulated but independent of hypoxia-inducible factor-mediated oxygen signaling pathway. More importantly, GDF15 induction was positively correlated to upregulation of ferroportin, the only cellular iron exporter, and to upregulation of ferritin heavy chain. CONCLUSIONS: Our study suggests that GDF15 induction helps suppress further activation of macrophages in stressful physiologic states as HLH, and is intimately implicated in the development of hyperferritinemia by modulating the hepcidin-ferroportin axis, resulting in enhanced ferroportin-mediated iron efflux. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.
Regulation of iron metabolism and innate immunity are tightly interlinked. The acute phase response to infection and inflammation induces alterations in iron homeostasis that reduce iron supplies to pathogens. The iron-hormone hepcidin is activated by such stimuli causing degradation of the iron exporter ferroportin and reduced iron release from macrophages, suggesting that hepcidin is the crucial effector of inflammatory hypoferremia. Here we report the discovery of an acute inflammatory condition that is mediated by Toll-like receptor (TLR) 2 and TLR6 and which induces hypoferremia in mice injected with TLR ligands. Stimulation of TLR2/TLR6 triggers profound decreases in ferroportin mRNA and protein expression in bone marrow-derived macrophages, liver and spleen of mice without changing hepcidin expression. Furthermore, C326S ferroportin mutant mice with a disrupted hepcidin/ferroportin regulatory circuitry respond to injection of the TLR2/6 ligands FSL1 or PAM3CSK4 by ferroportin down regulation and a reduction of serum iron levels. Our findings challenge the prevailing role of hepcidin in hypoferremia and suggest that rapid hepcidin-independent ferroportin down regulation in the major sites of iron recycling may represent a first line response to restrict iron access for numerous pathogens.
Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients with CKD
- Clinical journal of the American Society of Nephrology : CJASN
- Published over 1 year ago
Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, regulates iron metabolism, and reduces hepcidin, was evaluated in this phase 2b study for safety, efficacy, optimal dose, and dose frequency in patients with nondialysis CKD.
Hepcidin is a small cysteine rich peptide that regulates the sole known cellular iron exporter, ferroportin, effectively controlling iron metabolism. Contrary to humans, where a single hepcidin exists, many fish have two functionally distinct hepcidin types, despite having a single ferroportin gene. This raises the question of whether ferroportin is similarly regulated by the iron regulator Hamp1 and the antimicrobial Hamp2. In sea bass (Dicentrarchus labrax), iron overload prompted a downregulation of ferroportin, associated with an upregulation of hamp1, whereas an opposite response was observed during anemia, with no changes in hamp2 in either situation. During infection, ferroportin expression decreased, indicating iron withholding to avoid microbial proliferation. In vivo administration of Hamp1 but not Hamp2 synthetic peptides caused significant reduction in ferroportin expression, indicating that in teleost fish with two hepcidin types, ferroportin activity is mediated through the iron-regulator Hamp1, and not through the dedicated antimicrobial Hamp2. Additionally, in vitro treatment of mouse macrophages with fish Hamp1 but not Hamp2 caused a decrease in ferroportin levels. These results raise questions on the evolution of hepcidin and ferroportin functional partnership and open new possibilities for the pharmaceutical use of selected fish Hamp2 hepcidins during infections, with no impact on iron homeostasis.
Hereditary hemochromatosis (HH) is a group of genetic iron overload disorders that manifest with various symptoms, including hepatic dysfunction, diabetes, and cardiomyopathy. Classic HH type 1, which is common in Caucasians, is caused by bi-allelic mutations of HFE. Severe types of HH are caused by either bi-allelic mutations of HFE2 that encodes hemojuvelin (type 2A) or HAMP that encodes hepcidin (type 2B). HH type 3, which is of intermediate severity, is caused by bi-allelic mutations of TFR2 that encodes transferrin receptor 2. Mutations of SLC40A1 that encodes ferroportin, the only cellular iron exporter, causes either HH type 4A (loss-of-function mutations) or HH type 4B (gain-of-function mutations). Studies on these gene products uncovered a part of the mechanisms of the systemic iron regulation; HFE, hemojuvelin, and TFR2 are involved in iron sensing and stimulating hepcidin expression, and hepcidin downregulates the expression of ferroportin of the target cells. Phlebotomy is the standard treatment for HH, and early initiation of the treatment is essential for preventing irreversible organ damage. However, because of the rarity and difficulty in making the genetic diagnosis, a large proportion of patients with non-HFE HH might have been undiagnosed; therefore, awareness of this disorder is important.
Hypoxia-inducible factors (HIFs) are central mediators of cellular adaption to hypoxia. The heterodimeric HIF transcription factors consist of HIF-α and HIF-β, that form functional HIFs. Mammals contain HIF-1α, HIF-2α, and HIF-3α. HIFs play a key role in iron metabolism by regulating the expression of iron-related proteins, such as divalent metal transporter 1 (DMT1), ferroportin 1 (FPN1), duodenal cytochrome b (Dcytb), and transferrin receptor (TfR). Hepcidin and iron regulatory proteins (IRPs), the central mediators for systematic and intracellular iron homeostasis, are also regulated by HIFs. In this review, we summarized the regulatory effects of HIFs on iron-related proteins, thus providing insights into the control of HIFs as therapeutic strategies for some iron related disorders.
Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis, and its inhibition could be a favorable strategy for treating anemia of chronic disease (ACD). Here, we report the design, synthesis and structure-activity relationships (SAR) of a series of 4,6-disubstituted indazole compounds as hepcidin production inhibitors. The optimization study of multi-kinase inhibitor 1 led to the design of a potent and bioavailable hepcidin production inhibitor, 32 (DS28120313), which showed serum hepcidin-lowering effects in an interleukin-6-induced acute inflammatory mouse model.