Sex Differences in Hypertension: Where We Have Been and Where We Are Going

Ramirez, Lindsey A; Sullivan, Jennifer C.

doi:10.1093/ajh/hpy148

Cited by 160 publications

(119 citation statements)

References 68 publications

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“…ACE2 is located on the X chromosome, and RAAS activity has been reported to exhibit sex-specific differences (7,8). ACE2 converts angiotensin II (Ang II) to the vasodilatory peptide Ang-(1-7), angiotensin I to Ang-(1-9) (also cleaved to Ang-(1-7) by angiotensin converting enzyme (ACE) or neprilysin), and angiotensin A to alamandine (9), a peptide mediating similar actions as Ang- (1)(2)(3)(4)(5)(6)(7). Together, this non-classical arm of the RAAS counteracts the vasoconstrictive, proliferative and inflammatory effects of the classical RAAS, mediated by Ang II (generated from angiotensin I by the action of ACE).…”

Section: Introductionmentioning

confidence: 99%

RAAS blockade, kidney disease, and expression of ACE2, the entry receptor for SARS-CoV-2, in kidney epithelial and endothelial cells

Subramanian

Vernon

Slyper

et al. 2020

Preprint

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AbstractSARS-CoV-2, the coronavirus that causes COVID-19, binds to angiotensin-converting enzyme 2 (ACE2) on human cells. Beyond the lung, COVID-19 impacts diverse tissues including the kidney. ACE2 is a key member of the Renin-Angiotensin-Aldosterone System (RAAS) which regulates blood pressure, largely through its effects on the kidney. RAAS blockers such as ACE inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs) are widely used therapies for hypertension, cardiovascular and chronic kidney diseases, and therefore, there is intense interest in their effect on ACE2 expression and its implications for SARS-CoV-2 pathogenicity. Here, we analyzed single-cell and single-nucleus RNA-seq of human kidney to interrogate the association of ACEi/ARB use with ACE2 expression in specific cell types. First, we performed an integrated analysis aggregating 176,421 cells across 49 donors, 8 studies and 8 centers, and adjusting for sex, age, donor and center effects, to assess the relationship of ACE2 with age and sex at baseline. We observed a statistically significant increase in ACE2 expression in tubular epithelial cells of the thin loop of Henle (tLoH) in males relative to females at younger ages, the trend reversing, and losing significance with older ages. ACE2 expression in tLoH increases with age in females, with an opposite, weak effect in males. In an independent cohort, we detected a statistically significant increase in ACE2 expression with ACEi/ARB use in epithelial cells of the proximal tubule and thick ascending limb, and endothelial cells, but the association was confounded in this small cohort by the underlying disease. Our study illuminates the dynamics of ACE2 expression in specific kidney cells, with implications for SARS-CoV-2 entry and pathogenicity.

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Section: Introductionmentioning

confidence: 99%

RAAS blockade, kidney disease, and expression of ACE2, the entry receptor for SARS-CoV-2, in kidney epithelial and endothelial cells

Subramanian

Vernon

Slyper

et al. 2020

Preprint

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“…Other experimental studies have shown that estrogen alters the incidence of hypertension in ovariectomized female rats [33] and offsets the fact that these female animals are more reactive to angiotensin II stimulation than their male counterparts [31]. This is supported by the fact that there is a higher proportion of hypertension in men than in pre-menopausal women but an increased incidence of hypertension in post-menopausal women [34]. However, the mechanism underlying the effects of the sex hormones on blood pressure is not fully understood and requires further evaluation.…”

Section: Discussionmentioning

confidence: 96%

Identifying Interactions between Dietary Sodium, Potassium, Sodium–Potassium Ratios, and FGF5 rs16998073 Variants and Their Associated Risk for Hypertension in Korean Adults

et al. 2020

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Hypertension is affected by both genetic and dietary factors. This study aimed to examine the interaction between dietary sodium/potassium intake, sodium–potassium ratios, and FGF5 rs16998073 and link these with increased risk for developing hypertension. Using data from the Health Examinee (HEXA) Study of the Korean Genome and Epidemiologic Study (KoGES), we were able to identify a total of 17,736 middle-aged Korean adults who could be included in our genome-wide association study (GWAS) to confirm any associations between hypertension and the FGF5 rs16998073 variant. GWAS analysis revealed that the FGF5 rs16698073 variant demonstrated the strongest association with hypertension in this population. Multivariable logistic regression was used to examine the relationship between dietary intake of sodium, potassium, and sodium–potassium ratios and the FGF5 rs16998073 genotypes (AA, AT, TT) and any increased risk of hypertension. Carriers with at least one minor T allele for FGF5 rs16998073 were shown to be at significantly higher risk for developing hypertension. Male TT carriers with a daily sodium intake ≥2000 mg also demonstrated an increased risk for developing hypertension compared to the male AA carriers with daily sodium intake <2000 mg (adjusted odds ratio (AOR) = 2.41, 95% confidence intervals (CIs) = 1.84–3.15, p-interaction < 0.0001). Female AA carriers with a daily potassium intake ≥3500 mg showed a reduced risk for hypertension when compared to female AA carriers with a daily potassium intake <3500 mg (AOR = 0.75. 95% CIs = 0.58–0.95, p-interaction < 0.0001). Male TT carriers in the mid-tertile for sodium–potassium ratio values showed the highest odds ratio for hypertension when compared to male AA carriers in the lowest-tertile for sodium–potassium ratio values (AOR = 3.03, 95% CIs = 2.14–4.29, p-interaction < 0.0001). This study confirmed that FGF5 rs16998073 variants do place their carriers (men and women) at increased risk for developing hypertension. In addition, we showed that high daily intake of sodium exerted a synergistic effect for hypertension when combined with FGF5 rs16998073 variants in both genders and that dietary sodium, potassium, and sodium–potassium ratios all interact with FGF5 rs16998073 and alter the risk of developing hypertension in carriers of either gender among Koreans.

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“…However, Class 4 did not include participants with hypertension. Hypertension has been shown to be more prevalent in women [44][45][46]. Therefore, it may be related to the high number of male participants in this class.…”

Section: Discussionmentioning

confidence: 99%

Modifiable Risk Factor Possession Patterns of Dementia in Elderly with MCI: A 4-Year Repeated Measures Study

Katayama

Lee

Bae

et al. 2020

JCM

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This study clarified the patterns of possessing modifiable risk factors of dementia that can be corrected by the elderly who were primarily determined to have mild cognitive impairment (MCI), and then determined the relationship between retention patterns and outcomes from MCI through a 4-year follow-up study. The participants were 789 community-dwelling elders who were ≥65 years old with MCI at baseline. After 4 years, participants were classified into reverters and nonreverters, according to their cognitive function. Repeated measures analysis was performed after imputing missing values due to dropout. Nine modifiable risk factors at baseline were classified by latent class analysis. Subsequently, we performed binomial logistic regression analysis. The reversion rate of 789 participants was 30.9%. The possession patterns of modifiable risk factors among the elderly with MCI were classified into five patterns: low risk, psychosocial, health behavior, educational, and smoking factors. According to logistic regression analysis, the low risk factors class was more likely to recover from MCI to normal cognitive than the other classes (p < 0.05). These results may provide useful information for designing interventions to prevent cognitive decline and dementia in individuals with MCI.

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Sex Differences in Hypertension: Where We Have Been and Where We Are Going

Cited by 160 publications

References 68 publications

RAAS blockade, kidney disease, and expression of ACE2, the entry receptor for SARS-CoV-2, in kidney epithelial and endothelial cells

RAAS blockade, kidney disease, and expression of ACE2, the entry receptor for SARS-CoV-2, in kidney epithelial and endothelial cells

Identifying Interactions between Dietary Sodium, Potassium, Sodium–Potassium Ratios, and FGF5 rs16998073 Variants and Their Associated Risk for Hypertension in Korean Adults

Modifiable Risk Factor Possession Patterns of Dementia in Elderly with MCI: A 4-Year Repeated Measures Study

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