Regulated expression of hypoxia-inducible factors during postnatal and postpneumonectomy lung growth

We previously found increased expression of erythropoietin receptor (EPO-R) in peripheral dog lung during postnatal and postpneumonectomy (PNX) lung growth. To study the upstream regulation of EPO-R, we analyzed the expression of hypoxia-inducible factors (HIF)-1alpha, -2alpha, and -3alpha during postnatal lung growth in immature and mature (2.5 and 12 mo old, respectively) dogs and during compensatory lung growth 3 wk and 10 mo after right PNX. Relative to their respective controls, HIF-1alpha transcript was 52-95% higher in immature lungs and 284% higher in the remaining lung 3 wk post-PNX. HIF-2alpha transcript did not change during maturation but was 42% lower 3 wk post-PNX. HIF-3alpha transcript was 53-65% lower in both the immature lung and 3 wk post-PNX. Changes were no longer detectable 10 mo post-PNX. No change in HIF transcripts was observed in kidney and liver post-PNX. Consistent with the mRNA changes, HIF-1alpha protein was 120 and 196% higher in growing lungs and 3 wk post-PNX relative to their respective controls. Overexpression of HIF-1alpha in cultured HEK-293 cells increased endogenous expression of EPO-R protein. These results demonstrate regulated expression of the HIF system and parallel changes in HIF-1alpha and EPO-R expression during two types of lung growth. Because the normal growing lung is not hypoxic, the HIF system likely responds to other signals encountered during sustained lung strain.