Hypoxia rapidly activates HIF‐3α mRNA expression

ABSTRACT The role of the hypoxia‐inducible factor (HIF) subunits 1α and 1β in cellular response to hypoxia is well established, whereas little is known about HIF‐2α and HIF‐3α with respect to organ distribution and transcriptional regulation by hypoxia. We investigated mRNA levels of all HIF subunits and of their target genes erythropoietin (EPO) and glucose‐transporter 1 (GLUT1) in rats undergoing systemic hypoxia for 30 or 120 min by quantitative real‐time RT‐PCR. In normoxia, persistently high mRNA levels of all HIF subunits were detected in cerebral cortex, hippocampus, and lung; the heart contained the lowest amounts. Hypoxia did not affect mRNA levels of HIF‐1α, ‐1β, and ‐2α. HIF‐3α mRNA levels increased in all organs examined after 2 h of hypoxia. A significant rise of EPO and GLUT1 mRNA levels occurred in cortex, heart, liver, and kidney after 2 h of hypoxia, indicating activation of the HIF system. Protein levels of all HIF subunits, determined in brain and lung by immunoblotting, showed a marked increase corresponding to the duration of hypoxia. Our results suggest that induction at the transcriptional level is a unique feature of HIF‐3α, which therefore may represent a rapidly reacting component of the HIF system in protection against hypoxic damage.