A Quest for Erythropoietin Over Nine Decades

Abstract

The major research accomplishments of the author are described from the time of his PhD thesis work on the mechanism of cobalt polycythemia to the present day. His early work on the quest for the cell that produces erythropoietin (Epo) to his current work on oxygen sensing and signal transduction pathways involved in erythropoietin gene expression are reported. He describes his main research interest in the mechanism of cobalt polycythemia between 1954 and 1962 and his research on how hormones such as the glucocorticoids function in the regulation of erythropoiesis (1956)(1957)(1958)(1959)(1960)(1961)(1962). His major findings during this period were the discovery that hydrocortisone and corticosterone stimulated erythropoiesis (1958) and that cobalt increased erythropoietin production in the isolated perfused dog kidney (1961). He describes how he was led astray in some of his early studies on the cells in the kidney that produce erythropoietin, because of the less-developed technology available to him at that time; and how in situ hybridization and other molecular biology techniques enabled him to confirm some of the earlier work in mice by other investigators that interstitial cells in the kidney were the site of production of erythropoietin in the primate. His work in the controversial area of the mechanism of the anemia of end-stage renal disease is described in detail, as it pertains to Epo deficiency and suppressed erythroid progenitor cell response to Epo. He also discusses his recent work on signal transduction pathways (hypoxia, nitric oxide, adenosine, and C kinase) in oxygen sensing and Epo gene expression. Early EducationI was born in Tucapau (now Startex), South Carolina, in 1925. Tucapau was a textile mill town that enjoyed both hydroelectric and steam (generated by coalburning furnaces) power to run the mill. My father was attracted to Tucapau to play on their textile league baseball team because he was an outstanding baseball 1 0362-1642/98/0415

The glucocorticoid receptor is required for stress erythropoiesis

“…Further erythroid target genes of the GR in ebls are currently being identified (H. Beug and G. Schü tz, unpubl.). Steroids such as GCs also stimulate erythropoiesis indirectly by increasing Epo production in the kidney (Fisher 1998). The molecular basis for this is unclear, because regulatory elements for transcriptional control of Epo expression are only described for the transcription factors HIF and HNF-4 (Galson et al 1995;Wang and Semenza 1996;Guillemin and Krasnow 1997) but not for the GR.…”

Erythropoietin and blood doping

“…[2][3][4][5] The physiological stimulus for EPO production is tissue hypoxia, which, in the large majority of instances, is directly related to the number of circulating erythrocytes. 6 Thus, EPO and erythropoiesis are part of a negative feedback cycle that keeps tissue oxygen delivery within a narrow range by controlling the number of erythrocytes circulating in the blood.…”

Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice

“…Erythropoietin (EPO) is a hormone that is essential for the production of red blood cells (1). EPO is mainly produced in the kidney after birth, and its production is severely reduced in patients with chronic kidney disease (CKD) (2) with renal anemia.…”