Integrity of the prolyl hydroxylase domain protein 2:erythropoietin pathway in aging mice

Abstract

The central transcriptional response to hypoxia is mediated by the prolyl hydroxylase domain protein (PHD):hypoxia inducible factor (HIF) pathway. In this pathway, PHD prolyl hydroxylates and thereby negatively regulates the α-subunit of the transcription factor HIF (HIF-α). An important HIF target gene is that for erythropoietin (EPO), which controls red cell mass. Recent studies have identified PHD2 as the critical PHD isoform regulating the EPO gene. Other studies have shown that the inducibility of the HIF pathway diminishes as a function of age. Thus, an important question is whether the PHD2:EPO pathway is altered in the aging. Here, we employed a mouse line with a globally-inducible Phd2 conditional knockout allele to examine the integrity of the Phd2:Epo axis in young (six to eight months old) and aging (sixteen to twenty months old) mice. We find that acute global deletion of Phd2 results in a robust erythrocytosis in both young and aging mice, with both age groups showing marked extramedullary hematopoiesis in the spleen. Epo mRNA is dramatically upregulated in the kidney, but not in the liver, in both age groups. Conversely, other Hif targets, including Vegf, Pgk1, and Phd3 are upregulated in the liver but not in the kidney in both age groups. These findings have implications for targeting this pathway in the aging.