Prostanoid activation of erythropoiesis

A model is proposed for the role of the kidney in the control of erythropoietin production in which the initial trigger is an oxygen deficit created by anemia, hypobaria or ischemia. It is postulated that hypoxia creates a decrease in the oxygen level in a critical renal sensor cell, perhaps in the glomerular tuft, which eventually leads to the production of prostacyclin. It is possible that the endothelial cell in the glomerular tuft responds to this oxygen deficit to produce prostacyclin to trigger erythropoietin production. Recent studies on prostaglandin synthesis by human isolated glomeruli indicate that the most abundant prostanoid synthesized by the glomerular tuft cells was 6-keto PGF1 alpha, a metabolite of prostacyclin (PGI2). PGI2 has also been reported to be produced by isolated vascular endothelial cells. The mechanism by which hypoxia may initiate the synthesis and/or release of prostaglandins and prostacyclin in the renal cell has not been elucidated. Significant to erythropoietin production is the production by hypoxia of prostacyclin which eventually leads to the production of the metabolite 6-keto PGE1. We further propose that 6-keto PGE1 is the prostanoid which activates a specific cell membrane adenylate cyclase, causing the conversion of ATP to cyclic AMP. This is a very critical step in that there must be a sufficient amount of ATP remaining to generate cyclic AMP in order for erythropoietin biosynthesis to occur with the reduced level of ATP which may have caused a perturbation of the cell membrane. The elevated cyclic AMP leads to the activation of protein kinases which are essential in phosphorylating the lysosomal hydrolases released by hypoxia into the cytosol of the cell and may be the precursors of erythropoietin. Neutral proteases and lysosomal hydrolases, documented triggers of erythropoietin production, have been demonstrated to be elevated in the kidney after hypoxia. The mechanism of labilization and release of these enzymes from the renal lysosomes has been postulated to be related to increases in cyclic GMP levels in a renal cell. Hypoxia causes the release of renal lysosomal hydrolases which then undergo phosphorylation through activation by protein kinases following prostanoid stimulation of renal adenylate cyclase to generate cyclic AMP, resulting in increased biosynthesis of erythropoietin.