POLYCYTHEMIC RESPONSES TO HYPOXIA - MOLECULAR AND GENETIC MECHANISMS OF CHRONIC MOUNTAIN-SICKNESS

We examined erythropoietin (EPO) gene expression and EPO production du ring hypoxia in two Sprague-Dawley rat strains with divergent polycyth emic responses to hypoxia. Hilltop (H) rats develop severe polycythemi a, severe hypoxemia, and pulmonary artery hypertension. The H rats oft en die from a syndrome indistinguishable from chronic mountain sicknes s (CMS) in humans. Madison (M) rats develop polycythemia and pulmonary artery hypertension that is modest and suffer no excess mortality. We tested the hypothesis that these rat strains have different stimulus- response characteristics governing EPO production. Rats of each strain were exposed to hypoxia (0.5 atm, 73 Torr inspired Po-2), and renal t issue EPO mRNA and EPO levels, plasma EPO, ventilation, arterial and r enal venous blood gases, and indexes of renal function were measured a t fixed times during a 30-day hypoxic exposure. During extended hypoxi c exposure, H rats had significantly elevated renal EPO mRNA, renal EP O, and plasma EPO levels compared with M rats. Ventilatory responses a nd indexes of renal function were similar in the strains during the hy poxic exposure. H rats had greater arterial hypoxemia from the onset o f hypoxia and more severe renal tissue hypoxemia and greater polycythe mia after 14 days of hypoxic exposure. When EPO responses were express ed as functions of renal venous Po-2, the two strains appeared to lie on the same dose-response curves, but the responses of H rats were shi fted along the curve toward more hypoxic values. We conclude that H ra ts have significantly greater polycythemia secondary to poorer renal t issue oxygenation, but the stimulus-response characteristics governing EPO gene expression and EPO production do not seem to differ between M and H rats. Finally, the regulation of EPO levels during hypoxia occ urs primarily at the transcriptional level.