Chronic dexamethasone treatment suppresses hypertension development in the transgenic rat TGR(mREN2)27.

Abstract

The transgenic rat TGR(mREN2)27 is a monogenetic rat model in hypertension research. Integration of mouse Ren-2 gene into the rat genome led to fulminant hypertension despite suppressed plasma and kidney renin concentrations. Renin is highly expressed in extrarenal tissues, especially throughout the adrenal cortex. Because plasma and urinary corticosteroid concentrations are elevated during the development of hypertension in these rats, we investigated the effect of dexamethasone on blood pressure, adrenal renin and steroid metabolism. A daily injection of 100 micrograms/kg dexamethasone for 8 weeks was capable of suppressing the development of hypertension in the transgenic rats. The same regimen did not alter blood pressure in Sprague-Dawley control rats. Plasma concentrations of adrenocorticotrophic hormone (ACTH)-dependent steroids (corticosterone and 18-hydroxydeoxycorticosterone) decreased markedly in both strains treated with dexamethasone, but more pronouncedly in transgenic rats. Surprisingly, plasma aldosterone concentrations increased exclusively in the transgenic rats, and not in control rats, treated with dexamethasone. The decrease in corticosterone and 18-hydroxydeoxycorticosterone production was accompanied by a decrease in the abundance of the messenger RNA (mRNA) encoding the rate-limiting enzyme in steroidogenesis (P450scc cholesterol side-chain cleavage) and a decrease in the mRNA encoding P450c11 beta (11 beta-hydroxylase). The increase in aldosterone was accompanied by a massive increase in the abundance of the mRNA encoding zona glomerulosa-specific P450c11AS (aldosterone synthase), which was not increased in control rats. We conclude that ACTH-dependent steroids other than the mineralocorticoid aldosterone are responsible for the development of hypertension in the transgenic rat.