Differential effects of sex steroids in young and aged female mRen2.Lewis rats: A model of estrogen and salt-sensitive hypertension

Background: Male-female differences in the expression of hypertension and in end-organ damage are evident in both experimental models and human subjects, with males exhibiting a more rapid onset of cardiovascular disease and mortality than do females. The basis for these male-female differences is probably the balance of the complex effects of sex steroids (androgens, estrogen, progesterone) and their metabolites on the multiple regulatory systems that influence blood pressure (BP). A key target of estrogen and other steroids is likely to be the different components of the renin-angiotensin-aldosterone system (RAAS). Objective: The aim of this study was to review the current experimental evidence on the protective effects of estrogen in hypertensive models. Methods: The search terms estrogen, renin-angiotensin-aldosterone system, renin receptor, salt-sensitivity, end-organ damage, hypertension, kidney, mRen2.Lewis, and injury markers were used to identify relevant publications in the PubMed database (restricted to the English language) from January 1990 to October 2007. Results: In a new congenic model that expresses the mouse renin 2 gene (mRen2.Lewis), estrogen depletion (via ovariectomy [OVX]) in young rats was found to have a marked stimulatory effect on the progression of increased BP and cardiac dysfunction. Moreover, estrogen depletion exacerbated salt-sensitive hypertension and the extent of salt-induced cardiac and renal injury in young mRen2.Lewis rats, which probably reflected the inability to appropriately regulate various components of the RAAS. However, OVX in aged mRen2.Lewis rats conveyed renal protective effects from a high-salt diet compared with intact hypertensive littermates (64 weeks), and these effects were independent of changes in BP. Conclusion: These studies in hypertensive mRen2.Lewis rats underscored the influence of ovarian hormones on BP and tissue injury, as well as the plasticity of this response, apparently due to age and salt status.