The liver orchestrates systemic iron balance by producing and secreting hepcidin. Known as the iron hormone, hepcidin induces degradation of the iron exporter ferroportin to control iron entry into ...the bloodstream from dietary sources, iron recycling macrophages, and body stores. Under physiologic conditions, hepcidin production is reduced by iron deficiency and erythropoietic drive to increase the iron supply when needed to support red blood cell production and other essential functions. Conversely, hepcidin production is induced by iron loading and inflammation to prevent the toxicity of iron excess and limit its availability to pathogens. The inability to appropriately regulate hepcidin production in response to these physiologic cues underlies genetic disorders of iron overload and deficiency, including hereditary hemochromatosis and iron-refractory iron deficiency anemia. Moreover, excess hepcidin suppression in the setting of ineffective erythropoiesis contributes to iron-loading anemias such as β-thalassemia, whereas excess hepcidin induction contributes to iron-restricted erythropoiesis and anemia in chronic inflammatory diseases. These diseases have provided key insights into understanding the mechanisms by which the liver senses plasma and tissue iron levels, the iron demand of erythrocyte precursors, and the presence of potential pathogens and, importantly, how these various signals are integrated to appropriately regulate hepcidin production. This review will focus on recent insights into how the liver senses body iron levels and coordinates this with other signals to regulate hepcidin production and systemic iron homeostasis.
Iron is an essential element for numerous fundamental biologic processes, but excess iron is toxic. Abnormalities in systemic iron balance are common in patients with chronic kidney disease and iron ...administration is a mainstay of anemia management in many patients. This review provides an overview of the essential role of iron in biology, the regulation of systemic and cellular iron homeostasis, how imbalances in iron homeostasis contribute to disease, and the implications for chronic kidney disease patients.
Mechanisms of Anemia in CKD BABITT, Jodie L; LIN, Herbert Y
Journal of the American Society of Nephrology,
10/2012, Letnik:
23, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Anemia is a common feature of CKD associated with poor outcomes. The current management of patients with anemia in CKD is controversial, with recent clinical trials demonstrating increased morbidity ...and mortality related to erythropoiesis stimulating agents. Here, we examine recent insights into the molecular mechanisms underlying anemia of CKD. These insights hold promise for the development of new diagnostic tests and therapies that directly target the pathophysiologic processes underlying this form of anemia.
Iron is an essential nutrient that is critical for fundamental cellular and organismal processes including oxygen transport and energy generation. However, excess iron can catalyze the formation of ...toxic free oxygen radicals. Cellular and systemic iron homeostasis are therefore tightly regulated to titrate the iron supply to match iron needs. The master regulator of systemic iron homeostasis is the liver hormone hepcidin, which binds and degrades the iron exporter ferroportin to limit iron release from dietary sources and body stores. To maintain normal systemic iron homeostasis, liver hepcidin production is coordinated by a number of signals that communicate body iron needs. Iron deficiency and anemia suppress hepcidin production to increase iron availability for red blood cell production and other essential functions. Conversely, increases in serum or tissue iron stimulate hepcidin production to prevent iron overload. Inflammation also stimulates hepcidin production to restrict iron availability to infectious microorganisms. Abnormal regulation of the hepcidin‐ferroportin axis has a pathogenic role in most disorders of systemic iron homeostasis including the anemia of inflammation, the iron overload disorder hereditary hemochromatosis, and iron‐loading anemias such as beta‐thalassemia. We have discovered a key role for the bone morphogenetic protein (BMP)‐SMAD signaling pathway in controlling liver hepcidin transcription. This talk will present recent insights into how BMP‐SMAD signaling coordinates liver hepcidin transcription in response to body iron levels and the iron demand of red blood cell production to maintain systemic iron homeostasis.
Circulating levels of fibroblast growth factor 23 (FGF23) are elevated in patients with chronic kidney disease (CKD), but the mechanisms are poorly understood. Here we tested whether inflammation and ...iron deficiency regulate FGF23. In wild-type mice, acute inflammation induced by single injections of heat-killed Brucella abortus or interleukin-1β (IL-1β) decreased serum iron within 6 h, and was accompanied by significant increases in osseous Fgf23 mRNA expression and serum levels of C-terminal FGF23, but no changes in intact FGF23. Chronic inflammation induced by repeated bacteria or IL-1β injections decreased serum iron, increased osseous Fgf23 mRNA, and serum C-terminal FGF23, but modestly increased biologically active, intact FGF23 serum levels. Chronic iron deficiency mimicked chronic inflammation. Increased osseous FGF23 cleavage rather than a prolonged half-life of C-terminal FGF23 fragments accounted for the elevated C-terminal FGF23 but near-normal intact FGF23 levels in inflammation. IL-1β injection increased Fgf23 mRNA and C-terminal FGF23 levels similarly in wildtype and Col4a3ko mice with CKD but markedly increased intact FGF23 levels only in the CKD mice. Inflammation increased Fgf23 transcription by activating Hif1α signaling. Thus, inflammation and iron deficiency stimulate FGF23 production. Simultaneous upregulation of FGF23 cleavage in osteocytes maintains near-normal levels of biologically active, intact circulating FGF23, whereas downregulated or impaired FGF23 cleavage may contribute to elevated intact serum FGF23 in CKD.
The bone-secreted hormone fibroblast growth factor 23 (FGF23) has an essential role in phosphate homeostasis by regulating expression of the kidney proximal tubule sodium-phosphate cotransporters as ...well as parathyroid hormone levels. Induction of FGF23 early in chronic kidney disease (CKD) helps to maintain normal phosphorous levels. However, high FGF23 levels become pathological as kidney disease progresses and are associated with an increased risk of CKD progression, cardiovascular events, and death. The factors responsible for increasing FGF23 levels early in CKD are unknown, but recent work has proposed a role for inflammation and disordered iron homeostasis. Notably, FGF23 has recently been shown to elicit an inflammatory response and to display immunomodulatory properties. Here, we will review emerging evidence on the cross talk between inflammation, iron, FGF23, and bone and mineral metabolism and discuss the relevance for CKD patients.
Iron is a micronutrient essential for almost all organisms: bacteria, plants, and animals. It is a metal that exists in multiple redox states, including the divalent ferrous (Fe2+) and the trivalent ...ferric (Fe3+) species. The multiple oxidation states of iron make it excellent for electron transfer, allowing iron to be selected during evolution as a cofactor for many proteins involved in central cellular processes including oxygen transport, mitochondrial respiration, and DNA synthesis. However, the redox cycling of ferrous and ferric iron in the presence of H2O2, which is physiologically present in the cells, also leads to the production of free radicals (Fenton reaction) that can attack and damage lipids, proteins, DNA, and other cellular components. To meet the physiological needs of the body, but to prevent cellular damage by iron, the amount of iron in the body must be tightly regulated. Here we review how the liver is the central conductor of systemic iron balance and show that this central role is related to the secretion of a peptide hormone hepcidin by hepatocytes. We then review how the liver receives and integrates the many signals that report the body's iron needs to orchestrate hepcidin production and maintain systemic iron homeostasis.
Anemia is prevalent in patients with chronic kidney disease (CKD) and is associated with lower quality of life and higher risk of adverse outcomes, including cardiovascular disease and death. Anemia ...management in patients with CKD currently revolves around the use of erythropoiesis-stimulating agents and supplemental iron. However, many patients do not respond adequately and/or require high doses of these medications. Furthermore, recent clinical trials have shown that targeting higher hemoglobin levels with conventional therapies leads to increased cardiovascular morbidity and mortality, particularly when higher doses of erythropoiesis-stimulating agents are used and in patients who are poorly responsive to therapy. One explanation for the poor response to conventional therapies in some patients is that these treatments do not fully address the underlying cause of the anemia. In many patients with CKD, as with patients with other chronic inflammatory diseases, poor absorption of dietary iron and the inability to use the body's iron stores contribute to the anemia. Recent research suggests that these abnormalities in iron balance may be caused by increased levels of the key iron regulatory hormone hepcidin. This article reviews the pathogenesis of anemia in CKD, the role and regulation of hepcidin in systemic iron homeostasis and the anemia of CKD, and the potential diagnostic and therapeutic implications of these findings.
Bone morphogenetic protein 6 (BMP6) signaling in hepatocytes is a central transcriptional regulator of the iron hormone hepcidin that controls systemic iron balance. How iron levels are sensed to ...regulate hepcidin production is not known, but local induction of liver BMP6 expression by iron is proposed to have a critical role. To identify the cellular source of BMP6 responsible for hepcidin and iron homeostasis regulation, we generated mice with tissue-specific ablation of Bmp6 in different liver cell populations and evaluated their iron phenotype. Efficiency and specificity of Cre-mediated recombination was assessed by using Cre-reporter mice, polymerase chain reaction of genomic DNA, and quantitation of Bmp6 messenger RNA expression from isolated liver cell populations. Localization of the BMP co-receptor hemojuvelin was visualized by immunofluorescence microscopy. Analysis of the Bmp6 conditional knockout mice revealed that liver endothelial cells (ECs) expressed Bmp6, whereas resident liver macrophages (Kupffer cells) and hepatocytes did not. Loss of Bmp6 in ECs recapitulated the hemochromatosis phenotype of global Bmp6 knockout mice, whereas hepatocyte and macrophage Bmp6 conditional knockout mice exhibited no iron phenotype. Hemojuvelin was localized on the hepatocyte sinusoidal membrane immediately adjacent to Bmp6-producing sinusoidal ECs. Together, these data demonstrate that ECs are the predominant source of BMP6 in the liver and support a model in which EC BMP6 has paracrine actions on hepatocyte hemojuvelin to regulate hepcidin transcription and maintain systemic iron homeostasis.
•Endothelial Bmp6 conditional knockout mice exhibit hemochromatosis, whereas hepatocyte and macrophage Bmp6 conditional knockout mice do not.•Our data support a model in which EC Bmp6 has paracrine actions on hepatocyte hemojuvelin to regulate hepcidin production.
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