PHD1-3 oxygen sensors in vivo-lessons learned from gene deletions.

Abstract

Oxygen sensors enable cells to adapt to limited oxygen availability (hypoxia), affecting various cellular and tissue responses. Prolyl-4-hydroxylase domain 1-3 (PHD1-3; also called Egln1-3, HIF-P4H 1-3, HIF-PH 1-3) proteins belong to the Fe2+- and 2-oxoglutarate-dependent dioxygenase superfamily and utilise molecular oxygen (O2) alongside 2-oxoglutarate as co-substrate to hydroxylate two proline residues of α subunits of the dimeric hypoxia inducible factor (HIF) transcription factor. PHD1-3-mediated hydroxylation of HIF-α leads to its degradation and inactivation. Recently, various PHD inhibitors (PHI) have entered the clinics for treatment of renal anaemia. Pre-clinical analyses indicate that PHI treatment may also be beneficial in numerous other hypoxia-associated diseases. Nonetheless, the underlying molecular mechanisms of the observed protective effects of PHIs are only partly understood, currently hindering their translation into the clinics. Moreover, the PHI-mediated increase of Epo levels is not beneficial in all hypoxia-associated diseases and PHD-selective inhibition may be advantageous. Here, we summarise the current knowledge about the relevance and function of each of the three PHD isoforms in vivo, based on the deletion or RNA interference-mediated knockdown of each single corresponding gene in rodents. This information is crucial for our understanding of the physiological relevance and function of the PHDs as well as for elucidating their individual impact on hypoxia-associated diseases. Furthermore, this knowledge highlights which diseases may best be targeted by PHD isoform-selective inhibitors in case such pharmacologic substances become available.