Evidence for a hepatic-renal antagonism in the production of hepatic erythropoietin

A tandem perfusion of the liver and kidneys of hepatectomized (hepx) rats was performed to ascertain the precise levels and time of appearance of the previously reported hepatic erythropoietic factor (HEF) and its antagonist, the renal inhibitory factor (RIF). Hepatic erythropoietic factor is produced by the hepx animal and is capable of augmenting the hepatic erythropoietin (Ep) response to hypoxia when administered to normal rats, whereas RIF acts to diminish this Ep response. Renal inhibitory factor does not directly affect Ep but appears to alter its synthesis owing to an inhibition to HEF production and/or action. In the present study, levels of HEF and RIF were determined at different intervals following hepx by in situ perfusion of the livers and kidneys of these animals. Levels of HEF are significantly higher than controls in rats at 24 to 72 hrs post hepx whereas its antagonist, the RIF, is not detectable until between 48 and 72 hrs after hepx. Inhibition of RIF of the hepatic Ep response is nearly total by 96 hrs following surgery. In previous studies, an increase in the hepatic Ep response to hypoxia was noted from 24 to 72 hrs after hepx. Peak hepatic Ep levels occurred at 72 hrs post hepx and declined thereafter, manifesting near normal hepatic Ep levels at 96 hrs after hepx. The present study provides an explanation for these findings by demonstrating that production of Ep by the hepx animal is dependent on the relative levels of a stimulatory (HEF) and an inhibitory (RIF) factor.