RODENT MODELS FOR STUDYING STEROIDS AND HYPERTENSION - FROM FETAL DEVELOPMENT TO CELLS IN CULTURE

We have used several different approaches to study the role of steroid s in hypertension, including rodent in vivo models, transgenic animals , and cell culture systems. Using the developing rodent fetus as a mod el for the ontogeny of regulation of glucocorticoid and mineralocortic oid synthesis, we found that in the developing rodent fetus, expressio n of both P450scc (cholesterol side chain cleavage) and P450c11 beta ( 11 beta-hydroxylase) mRNAs occur early, before there is complete organ ization of the fetal adrenal. Even after the zones of the adrenal are evident, the fetal adrenal still does not express the glomerulosa-spec ific P450c11AS (aldosterone synthase) mRNA. Stimulating maternal adren al mineralocorticoid or glucocorticoid synthesis does not affect accum ulation of fetal adrenal steroidogenic mRNAs, suggesting that the rode nt fetal adrenal maybe somewhat transcriptionally quiescent in vivo. W e also used two different transgenic rodent systems to study the roles of steroids in hypertension. Using promoter-directed tumorigenesis in transgenic mice, we created transgenic mice that expressed SV40 T ant igen under control of the P450scc promoter. Massive adrenal tumors, bu t not gonadal tumors, developed in all transgenic mice, and cells from these tumors were easily cultured. Using a novel selection tactic, we obtained several adrenocortical cell lines which have distinct charac teristics, suggesting they were locked into various stages of differen tiation; both expression of steroidogenic mRNAs and the steroids synth esized differ among the lines. Regulation of steroid synthesis and mRN A abundance also varies among cell lines. Several cell lines also expr ess mouse renin, and its synthesis, secretion, and mRNA abundance is a lso hormonally regulated. In a second transgenic model, we used a tran sgenic rat (TGR) that expresses an additional renin-2 gene primarily i n the adrenal to study the role of adrenal renin in regulating adrenal steroidogenesis in vivo. Since plasma and urinary corticosteroid conc entrations are elevated throughout the development of hypertension in these animals, we studied the effect of ACTH and Dexamethasone (DEX) o n blood pressure and steroidogenesis. Daily injections of Dex suppress ed the development of hypertension in TGR, but did not alter blood pre ssure in Sprague-Dawley (SD) control rats. This reduction in blood pre ssure was associated with reductions in plasma concentrations of corti costerone and 18-OH-DOC and of P450scc and P450c11 beta mRNAs. Surpris ingly, plasma aldosterone concentrations and P450c11AS mRNA increased in TGR but not SD treated with Dex. Although Dex resulted in differenc es in the regulation of P450scc, P450c11 beta, and P450c11AS mRNAs bet ween TGR and SD rats, regulation of these mRNAs by ACTH was similar in both strains of rats. These data provide evidence for the important r ole of adrenal renin and corticosteroids in the development of hyperte nsion in TGR. Taken together, these model systems will continue to all ow us to study the varied roles that steroid hormones play in hyperten sion.