Molecular mechanisms of hepcidin regulation: implications for the anemia of CKD

Abstract

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.

Figure 1

Hepcidin is a central regulator of systemic iron homeostasis. Serum iron levels are determined by the balance of iron entry from intestinal absorption, macrophage iron recycling, and mobilization of hepatocyte stores, versus iron utilization, primarily by erythroid cells in the bone marrow. A peptide hormone secreted by the liver, hepcidin controls iron release into the plasma by downregulating cell-surface expression of the iron export protein ferroportin (FPN; encoded by the SLC40A1 gene) on absorptive enterocytes, macrophages, and hepatocytes. Hepcidin production is inhibited by erythropoetic drive and hypoxia, to ensure iron availability for erythropoiesis. Hepcidin production is stimulated by iron (via the hemochromatosis proteins HFE, hemojuvelin [HJV], and transferrin receptor 2 [TFR2]) as a negative feed back loop to maintain steady state iron levels. Hepcidin production is also stimulated by inflammation, thereby sequestering iron from invading pathogens in the setting of infection, but also causing the hypoferremia of anemia of chronic disease. Abbreviation: RBC, red blood cell.

Figure 2

Schematic diagram depicting the proposed role of bone morphogenetic protein (BMP) signaling pathway, HJV, HFE, and TFR2 in iron sensing and hepcidin regulation in the liver. In response to iron, bone morphogenetic protein 6 (BMP6) binds to the BMP co-receptor hemojuvelin (HJV) as part of the BMP6/HJV/BMPR complex on the hepatocyte membrane to activate the SMAD1/5/8 pathway. Activated SMAD complexes bind directly to BMP responsive elements (BMP-REs) on the hepcidin promoter to induce hepcidin transcription. Holotransferrin (TF-Fe) competes for HFE binding to transferrin receptor 1 (TFR1), causing HFE displacement to form a complex with TFR2 and TF-Fe to induce hepcidin expression, possibly through an interaction with the BMP6-HJV-SMAD signaling pathway and/or alternative signaling pathways such as the ERK1/2 pathway. In the setting of iron deficiency, the serine protease TMPRSS6 inhibits hepcidin expression by cleaving membrane-bound HJV to form soluble HJV, thereby inhibiting downstream SMAD signaling by loss of membrane-bound HJV and sequestration of BMP6 ligand. Abbreviations: BMPR, BMP receptor, TF, transferrin.

Figure 3

Schematic diagram depicting the molecular mechanisms by which inflammation activates hepcidin transcription in the liver. Inflammation mediated by cytokines (e.g., IL-6) leads to activation of the JAK/STAT3 pathway. Activated STAT3 binds directly to a STAT3-responsive element (STAT3-RE) on the hepcidin promoter to induce hepcidin transcription. The JAK/STAT3 pathway depends on an intact BMP responsive element (BMP-RE) that is adjacent to the STAT3-RE for full activity. Inflammation may also activate the endoplasmic reticulum (ER) stress pathway using a CREBH-responsive element (CREBH-RE) on the hepcidin promoter to induce hepcidin. Abbreviations: BMP, bone morphogenetic protein; CREBH, cyclic AMP response element-binding protein H; JAK, janus kinase; STAT3, activator of transcription 3.

Figure 4. Hepcidin levels in chronic kidney diease and end-stage renal diease patients

Hepcidin levels are elevated in chronic kidney disease and end-stage renal diease patients, and reflect the balance of stimulatory factors: reduced renal clearance (GFR, glomerular filtration rate), inflammation, and iron administration; and inhibitory factors: anemia, erythropoiesis-stimulating agent (ESA) administration, clearance by dialysis, and hypoxia.