Sex-related differences in hypertension and renal injury: Role of the renin angiotensin system

Sex differences in hypertension and tissue injury are evident in experimental models and human subjects, yet the mechanisms underlying this disparity remain equivocal. The prevalence of hypertension in the United States has increased over the past century and progresses at a faster rate in men than in premenopausal women. The renin-angiotensin system (RAS) contributes to the development and maintenance of hypertension. Angiotensin II (Ang II) and angiotensin-(1-7) are two peptides derived from the RAS that possess vasoconstrictive and vasodilatory actions, respectively. Ang II contributes to hypertension and effective antihypertensive treatments involve enzyme inhibition and receptor blockade to prevent the effects of Ang II. Estrogen may provide a protective effect in women because the hormone exerts an inhibitory action on Ang II production and activity. Therefore, the current studies sought to define the extent of female-male differences in the circulating and renal RAS of the mRen(2).Lewis, a monogenetic model of Ang II-dependent hypertension that overexpresses the mouse renin 2 (Ren-2) gene, and the control Lewis rats. Male mRen(2).Lewis rats have significantly higher blood pressure, plasma and renal Ang II than male Lewis rats. Furthermore, mRen(2).Lewis rats also exhibit a marked sex difference both in the extent of hypertension and Ang II that is not present in the Lewis strain. Plasma renin, angiotensin converting enzyme (ACE), and Ang I are lower in female mRen(2).Lewis as compared to male mRen(2).Lewis rats. In association with lower blood pressure, female mRen(2).Lewis expressed greater Ang-(1-7) suggesting a protective vasodilatory mechanism. Moreover, evaluation of the intrarenal RAS revealed a similar sex difference in the RAS of the mRen(2).Lewis that was not present in the Lewis strain. Renal Ang II was lower, while cortical neprilysin, an enzyme that degrades Ang II and generates Ang-(1-7) from Ang 1, was significantly higher in female versus male mRen(2).Lewis. Neprilysin is stimulated by estrogen and may contribute to lower blood pressure through the renal metabolism of Ang II, as well as the formation of Ang-(1-7). Therefore, we determined whether chronic administration of the neprilysin inhibitor SCH 39370 would increase blood pressure and Ang II levels in female mRen(2).Lewis rats. Following a two week treatment, blood pressure was significantly decreased by 20 mm Hg. Neither circulating nor urinary Ang II and Ang-(1-7) levels were altered by neprilysin inhibition. In conclusion, our studies revealed that the increased expression of renal neprilysin in the female mRen(2).Lewis rat does not contribute to the sex-dependent difference in blood pressure for this model of hypertension.