Oxygen-Regulation of Erythropoiesis and Iron Metabolism

The Haase Lab studies the cellular and molecular mechanisms that lead to the development of renal anemia. Anemia associated with CKD is due to a relative deficiency in renal erythropoietin (EPO) production, concomitant functional and/or absolute iron deficiency and resistance to EPO signaling, which is seen in the setting of inflammation.

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click here for a detailed review on renal anemia

Mechanisms of renal anemia. Shown is an overview of factors and conditions that contribute to the pathogeneis of renal anemia. The impaired ability of the kidney to produce EPO is indicated by a dashed line. Inflammatory cytokines suppress erythropoiesis in the BM and stimulate hepcidin production in the liver, which impacts iron absorption and mobilization negatively. Hepcidin is also maintained at higher levels by decreased errythroferrone production (dotted blue line), which is secondary to a reduction in erythroblast numbers due to EPO deficiency in renal failure. In patients with advanced CKD, the liver contributes significantly to serum EPO levels. The contribution of uremic toxins to the pathogenesis of renal anemia is only poorly understood. Uremic toxins have been shown to suppress erythroid colony formation in vitro as well as EPO transcription in hepatoma cells, the latter indicating possible suppressive effects on hepatic and renal EPO production in vivo (indicated by red line).

Over the last decade the Haase group has focused on investigating the role of HIF in the regulation of erythropoiesis and iron metabolism. We have generated multiple genetic models of anemia and polycythemia and have contributed to the development of drugs that are currently in clinical development for renal anemia (HIF stabilizers). Specifically, we have identified HIF-2 as the key regulator of renal EPO synthesis and have established that HIF coordinates erythropoiesis with iron metabolism by directly regulating iron uptake and release.

More recently, the Haase lab investigated the role of HIF in the regulation of hepcidin and was able to show that the hypoxic suppression of hepcidin occurs indirectly through HIF-2-mediated stimulation of erythropoiesis. We have now developed novel genetic models to further dissect the PHD/HIF axis in various renal cell populations and have begun to interrogate the hypoxic regulation of HIF-2 signaling in renal interstitial cells under physiologic and injury conditions.

HIF-dependent regulation of iron metabolism

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HIF-dependent regulation of iron metabolism. Schematic overview of HIF-regulated genes involved in iron metabolism shown in red. In the gut duodenal cytochrome b (DCYTB) reduces ferric iron (Fe3+) to its Fe2+, which enters enterocytes via the divalent metal transporter-1 (DMT1). DCYTB and DMT1 are both bona fide HIF-2-regulated genes. Release of iron into the circulation occurs via ferroportin (FPN), which is hepcidin-regulated but also HIF-inducible. In blood, iron is transported in complex with transferrin (TF) to the liver, cells of the reticulo-endothelial system (RES), bone marrow and other organs. Increased erythropoietic activity in the BM produces growth differentiation factor 15 (GDF15) and erythroferrone, which have been shown suppress hepcidin in hepatocytes. Inflammatory cytokines stimulate hepcidin production in the liver and lead to reduced ferroportin surface expression and hypoferremia.

Relevant Publications from the Haase Lab

  • Kobayashi H, Liu Q, Binns TC, Urrutia AA, Davidoff O, Kapitsinou PP, Pfaff AS, Olauson H, Wernerson A, Fogo AB, Fong GH, Gross KW, Haase VH. Distinct subpopulations of FOXD1 stroma-derived cells regulate renal erythropoietin. J Clin Invest. 2016 May 2;126(5):1926-38. PubMed PMID: 27088801; PubMed Central PMCID: PMC4855934.
  • Farsijani NM, Liu Q, Kobayashi H, Davidoff O, Sha F, Fandrey J, Ikizler TA, O’Connor PM, Haase VH. Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin. J Clin Invest. 2016 Apr 1;126(4):1425-37. PubMed PMID: 26927670; PubMed Central PMCID: PMC4811147.
  • Liu Q, Davidoff O, Niss K, Haase VH. Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis. J Clin Invest. 2012 Dec;122(12):4635-44. PubMed PMID: 23114598; PubMed Central PMCID: PMC3533545.
  • Rankin EB, Biju MP, Liu Q, Unger TL, Rha J, Johnson RS, Simon MC, Keith B, Haase VH. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest. 2007 Apr;117(4):1068-77. PubMed PMID: 17404621; PubMed Central PMCID: PMC1838939.