Canonical Renin-angiotensin System Research Articles

105 Fetal hypothyroidism dysregulates local hepatic and renal renin-angiotensin systems in a temporal manner

Abstract The renin-angiotensin system (RAS) is an essential endocrine system with roles in electrolyte balance, blood volume, and blood pressure. While the canonical RAS exerts systemic vasoregulatory effects through steps involving hepatic, renal, and pulmonary-derived compounds, there is also evidence of localized, independently acting RAS in organs such as the liver and kidney. Further, modulations in RAS resulting from fetal hypothyroidism have previously been documented, although the temporal specificity of this endocrine interaction is not well-characterized. Thus, the objective of the current study was to examine the time-dependency of modulations in local hepatic and renal RAS in a porcine model of fetal hypothyroidism. To achieve this, pregnant gilts (n = 24) were divided evenly into either a control (CON) or methimazole (MMI) treatment group, with the MMI group receiving 5 mgּ kg-1ּ d-1 of oral MMI treatment and the CON group receiving an equivalent sham carrier. Each group was further divided into four timepoints (n = 3/treatment at each timepoint), with treatment beginning on d 34, 45, 55, or 65 of gestation. After 21 d of treatment, and at d 55, 66, 76, and 86, respectively, the gilts were humanely euthanized, blood samples taken from all fetuses (n = 340), and thyroid, liver (LVR), and kidney (KID) collected from a subset of four fetuses per litter (n = 96). Confirmation of fetal hypothyroidism in the MMI group was accomplished via histological assessment of the thyroid and measurement of circulating thyroxine (T4) concentrations. Each MMI-treated fetus (n = 96) subset showed evidence of goitrous thyroid histology, with the absence of healthy eosinophilic colloid indicating successful disruption of the fetal hypothalamic-pituitary-thyroid axis. T4 assays performed on a similar subset of n = 96 fetuses showed that MMI treatment significantly reduced T4 concentrations within each timepoint relative to CON (P < 0.001 at all timepoints). Following confirmation of hypothyroidism, RNA was extracted from the fetal LVR and KID samples to allow for gene expression analysis by qPCR. Ct values were normalized, fold changes calculated using the 2-∆∆Ct method, and differences within timepoint determined using a Wilcoxon signed-rank test. AGT, the precursor to all bioactive RAS peptides, was significantly downregulated in LVR at d 66 (P = 0.014) and 76 (P < 0.001). ACE was significantly upregulated at d 76 in both LVR (P = 0.037) and KID (P = 0.005). No significant changes were observed for ACE2 in either tissue, or for renal REN. Finally, AGTR1, the receptor that mediates RAS effects, was significantly downregulated at d 55 in KID (P < 0.001) and d 76 in LVR (P = 0.023), while also being upregulated at d 86 in LVR (P = 0.033). Collectively, these results show that fetal hypothyroidism modulates RAS function in a gestational age-dependent manner, which may alter fetal development and subsequent postnatal physiology.

MUTUAL COMPLEMENTALLY RELATIONSHIP OF AT2 AND MAS RECEPTORS IN PROTECTIVE EFFECT AGAINST SKELETAL MUSCLE AGEING IN MICE

Objective: Increasing evidence suggests that the renin-angiotensin system (RAS) is a candidate for control aging-associated phenotypes. RAS have two distinct axes, which counter-regulate each other. One is canonical RAS axis composed of angiotensin II and AT1 receptor, another is non-canonical RAS axis, it's main components are angiotensin 1–7 and AT2 and Mas receptors. To elucidate whether non-canonical axis have protective effect against age-associated muscle weakness, we first tested with Mas KO mice. But we didn’t any significant difference in aging phenotype in Mas KO mice compared with wild-type (WT) mice (Clinical Science, 2019.). In this study, we focused on AT2 receptor, we tested skeletal muscle function of AT2 KO mice and AT2 / Mas double KO (DKO) mice. Design and method: AT2 KO mice, DKO mice and WT mice were used (n = 5–8). To assess serial change in motor function, we performed grip strength test in 6, 12, 18, 24 months old. At 24 months old, mice were sacrificed and extracted six kinds of skeletal muscles. Using skeletal muscles, wet weight, cross sectional area of myofiber, expression of RAS-associated, inflammatory-associated and senescence-associated genes were assessed. All of data are statically analyzed by using Dunnett's test. Results: DKO mice showed significant weaker grip strength than WT mice from the age of 18 months. Wet weights of soleus and Vastus muscle were lower in DKO than WT mice. Classical RAS associated genes (Renin, ACE, AT1), inflammatory-associated genes (MCP-1, IL-6, TGF beta-1) and senescence-associated genes (p16, p19) is highly expressed in vastus of DKO. Grip strength, wet weight of skeletal muscles, and gene expression levels in AT2KO mice are equivalent to WT mice. Cross sectional area of vastus myofiber is significantly lower in AT2KO and DKO than in WT. Conclusions: In summary, we observed exaggerated ageing phenotypes of skeletal muscles in DKO mice, while hardly any ageing phenotypes were observed neither in AT2KO mice nor Mas KO mice. Our data suggests AT2 and Mas receptors are mutual complementally relationship in protective roll against age-associated skeletal muscle weakness via blockade of canonical RAS axis.

Sex differences in COVID-19: candidate pathways, genetics of ACE2, and sex hormones.

Biological sex is increasingly recognized as a critical determinant of health and disease, particularly relevant to the topical COVID-19 pandemic caused by the SARS-CoV-2 coronavirus. Epidemiological data and observational reports from both the original SARS epidemic and the most recent COVID-19 pandemic have a common feature: males are more likely to exhibit enhanced disease severity and mortality than females. Sex differences in cardiovascular disease and COVID-19 share mechanistic foundations, namely, the involvement of both the innate immune system and the canonical renin-angiotensin system (RAS). Immunological differences suggest that females mount a rapid and aggressive innate immune response, and the attenuated antiviral response in males may confer enhanced susceptibility to severe disease. Furthermore, the angiotensin-converting enzyme 2 (ACE2) is involved in disease pathogenesis in cardiovascular disease and COVID-19, either to serve as a protective mechanism by deactivating the RAS or as the receptor for viral entry, respectively. Loss of membrane ACE2 and a corresponding increase in plasma ACE2 are associated with worsened cardiovascular disease outcomes, a mechanism attributed to a disintegrin and metalloproteinase (ADAM17). SARS-CoV-2 infection also leads to ADAM17 activation, a positive feedback cycle that exacerbates ACE2 loss. Therefore, the relationship between cardiovascular disease and COVID-19 is critically dependent on the loss of membrane ACE2 by ADAM17-mediated proteolytic cleavage. This article explores potential mechanisms involved in COVID-19 that may contribute to sex-specific susceptibility focusing on the innate immune system and the RAS, namely, genetics and sex hormones. Finally, we highlight here the added challenges of gender in the COVID-19 pandemic.

Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Rescue Memory Defects in Drosophila-Expressing Alzheimer's Disease-Related Transgenes Independently of the Canonical Renin Angiotensin System.

Alzheimer’s disease (AD) is a degenerative disorder that causes progressive memory and cognitive decline. Recently, studies have reported that inhibitors of the mammalian renin angiotensin system (RAS) result in a significant reduction in the incidence and progression of AD by unknown mechanisms. Here, we used a genetic and pharmacological approach to evaluate the beneficial effects of angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) in Drosophila expressing AD-related transgenes. Importantly, while ACE orthologs have been identified in Drosophila, other RAS components are not conserved. We show that captopril, an ACE-I, and losartan, an ARB, can suppress a rough eye phenotype and brain cell death in flies expressing a mutant human C99 transgene. Captopril also significantly rescues memory defects in these flies. Similarly, both drugs reduce cell death in Drosophila expressing human Aβ42 and losartan significantly rescues memory deficits. However, neither drug affects production, accumulation or clearance of Aβ42. Importantly, neither drug rescued brain cell death in Drosophila expressing human Tau, suggesting that RAS inhibitors specifically target the amyloid pathway. Of note, we also observed reduced cell death and a complete rescue of memory deficits when we crossed a null mutation in Drosophila Acer into each transgenic line demonstrating that the target of captopril in Drosophila is Acer. Together, these studies demonstrate that captopril and losartan are able to modulate AD related phenotypes in the absence of the canonical RAS pathway and suggest that both drugs have additional targets that can be identified in Drosophila.

Sex differences in cardiovascular actions of the renin-angiotensin system.

Cardiovascular disease (CVD) remains a worldwide public health concern despite decades of research and the availability of numerous targeted therapies. While the intrinsic physiological mechanisms regulating cardiovascular function are similar between males and females, marked sex differences have been established in terms of CVD onset, pathophysiology, manifestation, susceptibility, prevalence, treatment responses and outcomes in animal models and clinical populations. Premenopausal females are generally protected from CVD in comparison to men of similar age, with females tending to develop cardiovascular complications later in life following menopause. Emerging evidence suggests this cardioprotection in females is, in part, attributed to sex differences in hormonal regulators, such as the renin-angiotensin system (RAS). To date, research has largely focused on canonical RAS pathways and shown that premenopausal females are protected from cardiovascular derangements produced by activation of angiotensin II pathways. More recently, a vasodilatory arm of the RAS has emerged that is characterized by angiotensin-(1-7) [(Ang-(1-7)], angiotensin-converting enzyme 2 and Mas receptors. Emerging studies provide evidence for a shift towards these cardioprotective Ang-(1-7) pathways in females, with effects modulated by interactions with estrogen. Despite well-established sex differences, female comparison studies on cardiovascular outcomes are lacking at both the preclinical and clinical levels. Furthermore, there are no specific guidelines in place for the treatment of cardiovascular disease in men versus women, including therapies targeting the RAS. This review summarizes current knowledge on sex differences in the cardiovascular actions of the RAS, focusing on interactions with gonadal hormones, emerging data for protective Ang-(1-7) pathways and potential clinical implications for established and novel therapies.

G-Protein-Coupled Estrogen Receptor Agonist G1 Improves Diastolic Function and Attenuates Cardiac Renin-Angiotensin System Activation in Estrogen-Deficient Hypertensive Rats.

This study was aimed to clarify differences in how specific agonists of the 3 estrogen receptors (ERs) influence diastolic function and the renin-angiotensin system (RAS) after ovariectomy (OVX) in 24 female spontaneously hypertensive rat (SHR) undergoing bilateral OVX at 12 weeks of age. Eight weeks after surgery, rats were randomized (n = 6/group) to receive equipotent, daily treatments of one of the ER agonists (ERα agonist, propyl pyrazole trisphenol 94 μg/kg; ERβ agonist, diarylpropionitrile 58 μg/kg; G-protein-coupled estrogen receptor [GPER] agonist, G1 100 μg/kg), or vehicle (peanut oil). After 4 weeks of treatment, left ventricular function/structure and systemic/intracardiac pressure measurements were obtained by echocardiography and a fluid-filled catheter attached to a pressure transducer, respectively. Selective ER agonist treatment with G1 or propyl pyrazole trisphenol led to improvements in diastolic function after estrogen loss when compared with vehicle-treated OVX rats. Although mean arterial blood pressure was not overtly different among groups, chronic G1, but not the other ER ligands, enhanced the in vitro vasorelaxant responsiveness to acetylcholine in aortic rings. These favorable effects of G1 were further linked to reductions in cardiac angiotensin-converting enzyme activity, AT1R protein expression, and Ang II immunoreactivity. Activation of ERβ had no effect on cardiac function and did not alter components of the canonical cardiac RAS in comparison with vehicle-treated OVX SHR. These data imply that of the 3 ERs, GPER has a unique role in preserving diastolic function and favorably modulating the cardiac RAS independent of arterial pressure. Specifically, if GPER is pharmacologically activated, it could provide a therapeutic opportunity to limit the development and/or progression of diastolic dysfunction in hypertensive women after estrogen loss.