Erythropoietin is the major stimulus for erythropoiesis. It is a glycoprotein produced principally by fibroblast-like cells in the renal interstitium. Under hypoxic conditions both the alpha and beta subunits of hypoxia inducible factor 1 (HIF-1) are expressed, leading to subsequent erythropoietin gene transcription via the combined effects of hepatic nuclear factor 4 (HNF-4), and HIF-1-alpha and -beta. Erythropoietin, once formed, binds to its receptors on erythroid precursor cells. Under normal oxygen conditions, only the HIF-1-beta subunit is expressed. The alpha subunit undergoes proline hydroxylation in the presence of iron and oxygen by prolyl hydoxylase. The hydroxylated HIF-1-alpha subunit binds to von Hippel-Lindau protein and a ubiquitin ligase complex is activated. This leads to ubiquitination and subsequent degradation of HIF-1-alpha via proteosomes so that no erythropoietin is transcribed.

Loss of renal substance, with decreased erythropoietin production, results in a normochromic, normocytic anaemia. Conversely, erythropoietin secretion may be increased, with resultant polycythaemia, in patients with polycystic renal disease, benign renal cysts or renal cell carcinoma. Recombinant human erythropoietin has been biosynthesized and is available for clinical use, particularly in patients with renal failure.

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