Sex differences in the renin-angiotensin-aldosterone system and its roles in hypertension, cardiovascular, and kidney diseases

Abstract

Cardiovascular disease is a pathology that exhibits well-researched biological sex differences, making it possible for physicians to tailor preventative and therapeutic approaches for various diseases. Hypertension, which is defined as blood pressure greater than 130/80 mmHg, is the primary risk factor for developing coronary artery disease, stroke, and renal failure. Approximately 48% of American men and 43% of American women suffer from hypertension. Epidemiological data suggests that during reproductive years, women have much lower rates of hypertension than men. However, this protective effect disappears after the onset of menopause. Treatment-resistant hypertension affects approximately 10.3 million US adults and is unable to be controlled even after implementing ≥3 antihypertensives with complementary mechanisms. This indicates that other mechanisms responsible for modulating blood pressure are still unclear. Understanding the differences in genetic and hormonal mechanisms that lead to hypertension would allow for sex-specific treatment and an opportunity to improve patient outcomes. Therefore, this invited review will review and discuss recent advances in studying the sex-specific physiological mechanisms that affect the renin-angiotensin system and contribute to blood pressure control. It will also discuss research on sex differences in hypertension management, treatment, and outcomes.

Keywords: cardiovascular; hypertension; kidney; renin-Angiotensin system; sex differences.

Figure 1

Classical renin/ACE-dependent and non-renin/ACE-dependent pathways for Ang II formation, metabolism, and actions in cardiovascular and kidney tissues. (1) The classical angiotensinogen/renin/ACE/ANG II/AT₁ receptor axis. (2) The ANG II/APA/ANG III/AT₂ receptor/NO/cGMP axis. (3) The ANG I/ANG II/ACE2-Neprilysin/ANG (1–7)/Mas receptor axis. (4) The prorenin/renin/prorenin receptor (PRR or ATP6ap2)/MAP kinases ERK1/2/V-ATPase axis. (5) The ANG III/APN/ANG IV/AT₄ receptor/IRAP axis. Note that not only ACE but also chymase generate ANG II from ANG I, whereas neprilysin also cleaves ANG I to generate ANG (1-7). ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; APA, aminopeptidase A; APN, aminopeptidase N; IRAP, insulin-regulated aminopeptidase; PRR, prorenin receptor. Modified from reference (9) with permission.

Figure 2

Localization of Ang II type 1 (AT₁ or AT_1a) and type 2 receptors (AT₂) in the rat kidney using ¹²⁵I-labeled Ang II receptor autoradiography and opposing actions of AT₁ (AT_1a), AT₂, and/or AT (1-7) receptor activation in the kidney. (A) Shows the localization of AT₁ or AT_1a receptors with high levels in the glomerulus (g) and the inner stripe of the outer medulla corresponding to vasa recta bundles, and moderate levels in the proximal convoluted tubules (pct) in the cortex (C) and renomedullary interstitial cells (RMICs) in the inner stripe of the outer medulla between vasa recta bundles. The inner medulla (IM) expresses a very low level of AT₁ or AT_1a. (B) Shows the localization of AT₂ receptors with low levels in the outer cortex, corresponding to the glomeruli and the proximal tubules, and the inner stripe of the outer medulla, corresponding to vasa recta bundles and RMICs. (C) Shows the localization of the receptor binding for Ang (1-7) in the kidney primarily in the inner cortex corresponding to the proximal tubules. Red represents high level (H), whereas dark blue represents background levels (L). Modified from reference (30) with permission.

Figure 3

Localization of Ang II type 1 (AT₁ or AT_1a) and type 2 receptors (AT₂) in the bovine, monkey, and human adrenal glands using quantitative ¹²⁵I-labeled Ang II receptor autoradiography. (A,E,I) Represent total Ang II receptor binding; (B,F,J) represent AT₁ receptor binding in the presence of an excess concentration of the AT₂ receptor blocker PD123319 (10 µM); (C,G,K) represent AT₂ receptor binding in the presence of an excess concentration of the AT₁ receptor blocker losartan (10 µM); and (D,H,L) represent nonspecific binding in the presence of an excess concentration of unlabeled Ang II (10 µM), respectively. AT₁ receptors predominate in the zona glomerulosa cells (ZG) of the adrenal cortex where aldosterone is synthesized and release into the circulation (B,F,J), and the adrenal medulla (M). AT₂ receptors are low in the adrenal glands of bovine, monkey, and human adrenal glands (C,G,K). Red represents the highest level, whereas dark blue represents the background level of receptor binding. Modified from reference (32) with permission from the copyright holder.

Figure 4

Comparisons of basal systolic, diastolic, and mean arterial blood pressure and their responses to Ang II infusion with or without AT₁ (AT_1a) receptor blocker losartan between male and female wild-type (WT) and PT-Agtr1a^−/− mice. Proximal tubule-specific deletion of AT_1a receptors significantly decreased basal blood pressure similarly in male and female PT-Agtr1a^−/− mice under basal conditions, and significantly attenuated the hypertensive responses to Ang II similarly in both male and female PT-Agtr1a^−/− mice. No significant sex differences were found in basal blood pressure and its responses to Ang II with or without losartan treatment between male and female WT or between male and female PT-Agtr1a^−/− mice. *P < 0.05 or **P < 0.01 vs. control WT or PT-Agtr1a^−/− mice; ⁺P < 0.05 or ⁺⁺P < 0.01 vs. Ang II-infused male or female wild-type or PT-Agtr1a^−/− mice. Reproduced from reference (171) with permission.

Figure 5

Sex differences in basal systolic, diastolic, and mean arterial blood pressure and their responses to a high pressor dose of Ang II infusion, 1.5 mg/kg per day, intraperitoneal via osmotic minipump in conscious, adult male and female wild-type (WT) and PT-Nhe3^−/− (proximal tubule-specific NHE3 knockout) mice, as measured using the direct implanted telemetry technique. Please note the time-dependent increases in systolic, diastolic, and mean arterial blood pressure responses to Ang II infusion in male WT mice and significantly attenuated hypertensive responses to Ang II in male PT-Nhe3^−/− mice. However, systolic, diastolic, and mean arterial blood pressure responses to Ang II began to decrease 4 days after Ang II infusion in female PT-Nhe3^−/− mice, revealing significant sex differences in these mutant mice. (A–C) Male mice; whereas (D–F) female mice. **P < 0.01 vs. WT time-control group; ⁺⁺P < 0.01 vs. PT-Nhe3^−/− time-control group, respectively. Reproduced from reference (36) with permission.