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

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.

Genetic Deletion of AT1a Receptor or Na+/H+ Exchanger 3 Selectively in the Proximal Tubules of the Kidney Attenuates Two-Kidney, One-Clip Goldblatt Hypertension in Mice.

The roles of angiotensin II (Ang II) AT1 (AT1a) receptors and its downstream target Na+/H+ exchanger 3 (NHE3) in the proximal tubules in the development of two-kidney, 1-clip (2K1C) Goldblatt hypertension have not been investigated previously. The present study tested the hypothesis that deletion of the AT1a receptor or NHE3 selectively in the proximal tubules of the kidney attenuates the development of 2K1C hypertension using novel mouse models with proximal tubule-specific deletion of AT1a receptors or NHE3. 2K1C Goldblatt hypertension was induced by placing a silver clip (0.12 mm) on the left renal artery for 4 weeks in adult male wild-type (WT), global Agtr1a−/−, proximal tubule (PT)-specific PT-Agtr1a−/− or PT-Nhe3−/− mice, respectively. As expected, telemetry blood pressure increased in a time-dependent manner in WT mice, reaching a maximal response by Week 3 (p < 0.01). 2K1C hypertension in WT mice was associated with increases in renin expression in the clipped kidney and decreases in the nonclipped kidney (p < 0.05). Plasma and kidney Ang II were significantly increased in WT mice with 2K1C hypertension (p < 0.05). Tubulointerstitial fibrotic responses were significantly increased in the clipped kidney (p < 0.01). Whole-body deletion of AT1a receptors completely blocked the development of 2K1C hypertension in Agtr1a−/− mice (p < 0.01 vs. WT). Likewise, proximal tubule-specific deletion of Agtr1a in PT-Agtr1a−/− mice or NHE3 in PT-Nhe3−/− mice also blocked the development of 2K1C hypertension (p < 0.01 vs. WT). Taken together, the present study provides new evidence for a critical role of proximal tubule Ang II/AT1 (AT1a)/NHE3 axis in the development of 2K1C Goldblatt hypertension.

Post-weaning Exposure to High-Fat Diet Induces Kidney Lipid Accumulation and Function Impairment in Adult Rats.

Aim: We investigated the kidney morphofunctional consequences of high-fat diet intake since post-weaning in adult rats. Main Methods: Male Wistar rats were divided into two groups: ND (normal diet; n = 10) and HD (high-fat diet; n = 10). The high-fat diet was introduced post-weaned and animals were followed for 8 weeks. Key Findings: HD group did not change body weight gain even though food consumption has decreased with no changes in caloric consumption. The HD group showed glucose intolerance and insulin resistance. The glomerular filtration rate (GFR) was decreased in vivo (ND: 2.8 ± 1.01; HD: 1.1 ± 0.14 ml/min) and in the isolated perfusion method (34% of decrease). Renal histological analysis showed a retraction in glomeruli and an increase in kidney lipid deposition (ND: 1.5 ± 0.17 HD: 5.9 ± 0.06%). Furthermore, the high-fat diet consumption increased the pro-inflammatory cytokines IL-6 (ND: 1,276 ± 203; HD: 1,982 ± 47 pg/mL/mg) and IL-1b (ND: 97 ± 12 HD: 133 ± 5 pg/mL/mg) without changing anti-inflammatory cytokine IL-10. Significance: Our study provides evidence that high-fat diet consumption leads to renal lipid accumulation, increases inflammatory cytokines, induces glomeruli retraction, and renal dysfunction. These damages observed in the kidney could be associated with an increased risk to advanced CKD in adulthood suggesting that reduction of high-fat ingestion during an early period of life can prevent metabolic disturbances and renal lipotoxicity.