Erythropoietin (Epo) is a glycoprotein hormone which stimulates the proliferation and differentiation of erythroid progenitor cells in the bone marrow. In adults, Epo is mainly produced by interstitial fibroblasts in the kidneys. Epo expression increases in response to a decrease of tissue oxygenation. The human cell line HK120 has been isolated from a renal carcinoma and expresses markers specific for interstitial fibroblasts. Hypoxia induced Epo mRNA expression as well as the release of biologically active Epo. Of main importance in the hypoxia induced gene expression is the transcription factor hypoxia-inducible factor (HIF). HIF consists of a common constitutive b-subunit and a different oxygen- regulated a-subunit (HIF-1a, HIF-2a, HIF-3a). In HK120 acute hypoxia caused an activation of HIF- 1a, chronic hypoxia in contrast caused an activation of HIF-2a. By siRNA approach and ChIP assay we found that hypoxia- induced Epo expression is under the control of both HIF transcription factor isoforms (HIF-1 and HIF-2). Based on the oxygen dependent regulation of the Epo expression and the expression of markers specific for renal fibroblasts, we propose HK120 as the first cell model that will enable us to study the molecular mechanisms of renal specific Epo expression.