Hypoxia in vivo inhibits aldosterone synthesis and aldosterone synthase mRNA in rats

Hypoxia leads to a decrease in aldosterone that cannot be entirely explained by extrinsic controllers of adrenal function. We have shown that acute hypoxia attenuates aldosterone synthesis via a direct inhibition of the function of the aldosterone enzyme pathway. The mechanism of the sustained decrease in aldosterone during chronic hypoxia is unknown. The present study evaluated the hypothesis that chronic hypoxia leads to a decrease in the expression of the steroidogenic enzyme P-450c11AS unique to the aldosterone pathway. Rats were exposed to 3 days of normoxia, moderate hypoxia (12% O₂), or severe hypoxia (10% O₂). Adrenal glands were removed and prepared for biochemical analysis of steroidogenesis in vitro (dispersed capsular cells) and for measurement of steady-state enzyme mRNA levels by reverse- transcription competitive polymerase-chain reaction (RT-cPCR) and by in situ hybridization histochemistry (ISHH). Moderate hypoxia had no effect on steroidogenesis. Adrenal cells from rats exposed to severe hypoxia demonstrated a decreased conversion of corticosterone to aldosterone (late pathway catalyzed by P-450c11AS) without a change in the other mitochondrial cytochrome P-450 enzyme activities. Adrenal cells from rats exposed to hypoxia also demonstrated a three- to fourfold decrease in P-450c11AS mRNA without a change in the other mitochondrial cytochrome P-450 enzymes mRNAs, as determined by either RT-cPCR or ISHH. We conclude that relatively short- term chronic hypoxia in rats leads to a decrease in aldosteronogenesis by decreasing the expression of the gene for the late-pathway enzyme unique to the aldosterone pathway (P-450c11AS).