Sex differences in the metabolic effects of the renin-angiotensin system

White, Melissa; Fleeman, Rebecca M.; Arnold, Amy C.

doi:10.1186/s13293-019-0247-5

Cited by 78 publications

(96 citation statements)

References 229 publications

(316 reference statements)

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“…Can this be due in part to less inhibition by AngII in the ArcN? In support, as reviewed previously [2,28,126,127], (1) in males, obesity increased components of the hypertensive arm of the RAS, AngII, and AT1R, but decreased components of the antihypertensive arm, Ang-(1-7) and ACE2. In females, obesity had the opposite effects (increased Ang-(1-7) and ACE2; no increase in AngII) [99].…”

Section: Mechanisms For the Differential Impact Of Obesity In The Arcsupporting

confidence: 76%

Obesity: sex and sympathetics

2020

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Obesity increases sympathetic nerve activity (SNA) in men, but not women. Here, we review current evidence suggesting that sexually dimorphic sympathoexcitatory responses to leptin and insulin may contribute. More specifically, while insulin increases SNA similarly in lean males and females, this response is markedly amplified in obese males, but is abolished in obese females. In lean female rats, leptin increases a subset of sympathetic nerves only during the high estrogen proestrus reproductive phase; thus, in obese females, because reproductive cycling can become impaired, the sporadic nature of leptin-induced sympathoexcitaton could minimize its action, despite elevated leptin levels. In contrast, in males, obesity preserves or enhances the central sympathoexcitatory response to leptin, and current evidence favors leptin's contribution to the well-established increases in SNA induced by obesity in men. Leptin and insulin increase SNA via receptor binding in the hypothalamic arcuate nucleus and a neuropathway that includes arcuate neuropeptide Y (NPY) and proopiomelanocortin (POMC) projections to the paraventricular nucleus. These metabolic hormones normally suppress sympathoinhibitory NPY neurons and activate sympathoexcitatory POMC neurons. However, obesity appears to alter the ongoing activity and responsiveness of arcuate NPY and POMC neurons in a sexually dimorphic way, such that SNA increases in males but not females. We propose hypotheses to explain these sex differences and suggest areas of future research.

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Section: Mechanisms For the Differential Impact Of Obesity In The Arcsupporting

confidence: 76%

Obesity: sex and sympathetics

2020

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“…In female mice, HFD increased adipose tissue ACE2 which was reversed by ovariectomy implying that estrogen increases ACE2 expression and activity in adipose tissue and kidneys. Furthermore global deficiency of the ACE2 gene increased HFD-induced obesity hypertension in male mice ( 126 , 127 ). Importantly, ovariectomy or treatment with an ER antagonist in SARS-CoV infected female mice increased the mortality rate therefore, suggesting a protective effect for the ER signaling pathway in mice ( 3 ).…”

Section: Immune Responsementioning

confidence: 99%

What’s Sex Got to Do With COVID-19? Gender-Based Differences in the Host Immune Response to Coronaviruses

et al. 2020

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The novel severe acute respiratory syndrome coronavirus 2, the cause of the coronavirus disease 2019 (COVID-19) pandemic, has ravaged the world, with over 22 million total cases and over 770,000 deaths worldwide as of August 18, 2020. While the elderly are most severely affected, implicating an age bias, a striking factor in the demographics of this deadly disease is the gender bias, with higher numbers of cases, greater disease severity, and higher death rates among men than women across the lifespan. While pre-existing comorbidities and social, behavioral, and lifestyle factors contribute to this bias, biological factors underlying the host immune response may be crucial contributors. Women mount stronger immune responses to infections and vaccinations and outlive men. Sex-based biological factors underlying the immune response are therefore important determinants of susceptibility to infections, disease outcomes, and mortality. Despite this, gender is a profoundly understudied and often overlooked variable in research related to the immune response and infectious diseases, and it is largely ignored in drug and vaccine clinical trials. Understanding these factors will not only help better understand the pathogenesis of COVID-19, but it will also guide the design of effective therapies and vaccine strategies for gender-based personalized medicine. This review focuses on sex-based differences in genes, sex hormones, and the microbiome underlying the host immune response and their relevance to infections with a focus on coronaviruses.

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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 ofACE2, 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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Sex differences in the metabolic effects of the renin-angiotensin system

Cited by 78 publications

References 229 publications

Obesity: sex and sympathetics

Obesity: sex and sympathetics

What’s Sex Got to Do With COVID-19? Gender-Based Differences in the Host Immune Response to Coronaviruses

RAAS blockade, kidney disease, and expression ofACE2, the entry receptor for SARS-CoV-2, in kidney epithelial and endothelial cells

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