Mechanisms of extrarenal erythropoietin (Ep) production.

Evidence is presented for production, by the subtotally hepatectomized (hepx) rat, of a factor which induces morphological and physiological hyperactivity of the Kupffer (K) cells and increased formation of Ep by the regenerating liver. This factor, originally termed hepatopoietin (Hp), and more recently the hepatic erythropoietic factor (HEF), is detectable in higher concentration in the hepatic venous blood than in blood draining other organs, thus supporting its hepatic origin. Production of the HEF is best related to hyperactivity of the K cells and not to the parenchymal (P) cells. The HEF can be demonstrated by administering serum from hepx donors to normal rats which respond with increased production of Ep when nephrectomized (nephrx) and rendered hypoxic. Removal of the kidneys from hepx donors further augments the Ep response to this serum in recipients. Subtotal hepx also evokes the production of a renal inhibitory factor (RIF) which reduces the ability of the liver to function as an extrarenal source of Ep. This inhibitor is found in renal venous blood and not in blood draining other organs. It is suggested that the RIF reduces the hepatic Ep response to hypoxia by diminishing the production and/or activity of the HEF. The RIF possesses no anti-Ep activity and its appearance and actions are not influenced by accumulation of metabolic wastes (as in the nephrx or ureterally-ligated rat). Erythroblastic nests have been observed in regenerating livers at 24-48 hr after subtotal hepx. It would seem that removal of a considerable part of the liver, which stimulates hepatic regeneration, confers upon this organ an increased ability to produce Ep and to function as a hematopoietic inductive microenvironment (HIM) for erythropoiesis.