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MOLECULAR PHARMACOLOGY 51:201-208 (1997).

-Adrenoceptor Activation-Induced Placental Prorenin Secretion Is Mediated by Increased Renin Messenger RNA and Protein Synthesis

Gregory J. Downing, Bingfang Yan, and Alan M. Poisner

Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160

Activation of -adrenoceptors has been shown to promote renin secretion in both human kidney and placenta. In kidney, the enhanced secretion is immediately observed, and mobilization of renin in the storage granules accounts for such a rapid response. In contrast, the enhanced secretion in placenta is delayed for 6-12 hr after receptor activation and consists almost entirely of the renin precursor prorenin. It is hypothesized that newly synthesized rather than stored enzyme is responsible for the enhanced secretion in human placenta. To test this hypothesis, placental explants were cultured in the presence or absence of the protein synthesis inhibitor cycloheximide, and prorenin concentrations in the tissue and medium were measured. Dobutamine and terbutaline, ₁- and ₂-adrenoceptor agonists, evoked 17- and 5-fold increases in secretion, respectively. Tissue content of prorenin in response to the treatment was increased by a similar magnitude, yet values were consistently <10% of medium concentrations. The increases in prorenin concentrations in both medium and tissue, however, were markedly attenuated by cycloheximide, suggesting that prorenin synthesis in response to -adrenoceptor activation is required. Reverse transcription coupled with polymerase chain reaction revealed that renin mRNA levels were increased by 3-8-fold and occurred before increases in tissue and medium prorenin, indicating that increased renin mRNA levels are responsible for the increased synthesis of prorenin. Explants cultured in the presence of actinomycin D, an inhibitor of transcription, did not show the agonist-induced prorenin mRNA levels or enhancement of its secretion. The peak levels of renin mRNA were reached after 6 hr of incubation, were sustained at similar levels after 24 hr, and were not affected by cycloheximide. These findings are consistent with the notion that enhancement of renin mRNA and de novo protein synthesis are required for prorenin secretion induced by activation of placental -adrenoceptors.