Relationship of renin‐angiotensin system polymorphisms with ambulatory and central blood pressure in patients with hypertension

Han, Wei; Sun, Ning; Chen, Lianghua; Jiang, Suping; Chen, Yunchao; Tian, Hui; Zhang, Ke; Han, Xiao

doi:10.1111/jch.13061

Cited by 5 publications

(5 citation statements)

References 27 publications

(49 reference statements)

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“…The systemic RAS is an endocrine system with important roles in regulating blood pressure and electrolyte homeostasis ( Ahn et al, 2017 ; Han et al, 2017 ). Various organs and tissues, including bone, have also been shown to have local tissue-specific RAS.…”

Section: Discussionmentioning

confidence: 99%

“…The systemic renin–angiotensin system (RAS) has been widely investigated because of its roles in the regulation of blood pressure, electrolyte homeostasis, and the development of hypertension ( Ahn et al, 2017 ; Han et al, 2017 ). Several human studies suggested that hypertension is associated with low bone mineral density and increased risk of fracture ( Li et al, 2017 ; Lian et al, 2017 ; Ye et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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Salt-Sensitive Hypertension Induces Osteoclastogenesis and Bone Resorption via Upregulation of Angiotensin II Type 1 Receptor Expression in Osteoblasts

Pramusita

Kitaura

Ohori

et al. 2022

Front. Cell Dev. Biol.

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Hypertension is a chronic-low grade inflammatory disease, which is known to be associated with increased bone loss. Excessive activity of the local renin–angiotensin system (RAS) in bone leads to increased bone resorption. As inflammatory cytokines may activate RAS components, we hypothesized that the elevated proinflammatory cytokine levels in hypertension activate bone RAS and thus lead to increased bone resorption. To investigate whether salt-sensitive hypertension (SSHTN) induces osteoclastogenesis and bone resorption, we generated a model of SSHTN in C57BL/6J mice by post-Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME) high-salt challenge. SSHTN led to the reduction of distal femur trabecular number and bone volume fraction, while trabecular separation of femoral bone showed a significant increase, with no change in cortical thickness. Histomorphometric examination showed a significant reduction in trabecular bone volume fraction with an increased number of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive cells and increased osteoclast surface fraction in the trabecular distal femur of hypertensive mice. Furthermore, analysis of gene expression in bone tissue revealed that TRAP and RANKL/OPG mRNA were highly expressed in hypertensive mice. TNF-α and angiotensin II type 1 receptor (AGTR1) mRNA and protein expression were also upregulated in SSHTN mice. These observations suggested that TNF-α may have an effect on AGTR1 expression leading to osteoclast activation. However, TNF-α stimulation did not promote AGTR1 mRNA expression in osteoclast precursors in culture, while TNF-α increased AGTR1 mRNA expression in osteoblast culture by activation of downstream p38. Angiotensin II was also shown to increase TNF-α-induced RANKL/OPG mRNA expression in primary osteoblast culture and osteoclastogenesis in a TNF-α-primed osteoblast and osteoclast precursor co-culture system. In addition, local injection of lipopolysaccharide into the supracalvariae of SSHTN mice markedly promoted osteoclast and bone resorption. In conclusion, mice with SSHTN show increased osteoclastogenesis and bone resorption due mainly to increased TNF-α and partly to the upregulation of AGTR1 in osteoblasts.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Salt-Sensitive Hypertension Induces Osteoclastogenesis and Bone Resorption via Upregulation of Angiotensin II Type 1 Receptor Expression in Osteoblasts

Pramusita

Kitaura

Ohori

et al. 2022

Front. Cell Dev. Biol.

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“…However, significant genotype-sex interactions were detected only among Mexican Americans (positive associations with SBP and hypertension in women, but not in men), while this was not observed for non-Hispanic white persons and non-Hispanic black persons. Multivariate regression analysis by Han et al (2017) demonstrated that the ACE DD genotype was independently associated with 24□hour SBP, 24□hour DBP, central SBP, and central augmentation index in Chinese patients recruited at Shandong Provincial Hospital in the Jinan area. Thus, it can be concluded that the influence of variation in the ACE gene on interindividual variation in blood pressure is dependent on contexts that are indexed by gender, age, and measures of body size (Turner et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Mathematical modeling of the influence ofACE I/Dpolymorphism on blood pressure and antihypertensive therapy

Kutumova,

Kovaleva,

Sharipov

et al. 2024

Preprint

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The angiotensin converting enzyme (ACE) gene (ACE) insertion/deletion (I/D) polymorphism has attracted much attention in recent years, as it raises the hope of personalizing ACE inhibitor therapy to optimize its efficiency and reduce side effects for genetically distinct subgroups. However, the extent of its influence among these subgroups remains inconclusive. Therefore, we extended our computational model of blood pressure regulation to investigate the effect of theACE I/Dpolymorphism on hemodynamic parameters in humans and antihypertensive therapy. The model showed that the dependence of blood pressure on serum ACE activity is a function of saturation. Hence, a possible reason for the lack of association betweenACE I/Dand blood pressure levels could be a fairly high ACE activity in populations. Additionally, in an extended model simulating the effects of different classes of antihypertensive drugs, we explored the relationship betweenACE I/Dand the efficacy of inhibitors of the renin-angiotensin-aldosterone system. The model predicted that the response of cardiovascular and renal parameters to treatment directly depends on ACE activity. However, significant differences in parameter changes were observed only between groups with high and low ACE levels, whileACE I/Dgenotypes within the same group had similar changes in absolute values. We conclude that a single genetic variant is responsible for only a small fraction of heredity in treatment success, so its predictive value is limited.

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“…Blood pressure and electrolyte balance are tightly controlled by the renin-angiotensin system (RAS). Hypertension is significantly influenced by RAS activation ( 26 , 27 ). RAS is a hormonal cascade in which renin from the kidney cleaves angiotensinogen from the liver into inactive angiotensin (ANG) I.…”

Section: Introductionmentioning

confidence: 99%

“…Pro-inflammatory chemicals including IL-6 and TNF-a, which encourage bone resorption, is further stimulated by ANG II. Several studies showed angiotensin II receptor blockers (ARB) bind to AT1R and block ANG II, preventing pathological changes (27)(28)(29)(30)(31).…”

Section: Introductionmentioning

confidence: 99%

Azilsartan inhibits inflammation-triggered bone resorption and osteoclastogenesis in vivo via suppression of TNF-α expression in macrophages

Fan,

Kitaura,

Ren

et al. 2023

Front. Endocrinol.

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IntroductionHypertension is a major risk factor for cardiovascular disease (CVD) and is associated with increased bone loss due to excessive activity of the local renin-angiotensin system (RAS). Angiotensinogen/Angiotensin (ANG) II/Angiotensin II type 1 receptor (AT1R) axis is considered as the core axis regulating RAS activity. Azilsartan is an FDA-approved selective AT1R antagonist that is used to treat hypertension. This study aimed to determine whether azilsartan affects formation of osteoclast, resorption of bone, and the expression of cytokines linked with osteoclastogenesis during lipopolysaccharide (LPS)-triggered inflammation in vivo.MethodsIn vivo, following a 5-day supracalvarial injection of LPS or tumor necrosis factor-alpha (TNF-α) with or without azilsartan, the proportion of bone resorption and the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells, which are identified as osteoclasts on mice calvariae were counted. The mRNA expression levels of TRAP, cathepsin K, receptor activator of NF-κB ligand (RANKL), and TNF-α were also evaluated. In vitro, the effect of azilsartan (0, 0.01, 0.1, 1, and 10 μM) on RANKL and TNF-α-triggered osteoclastogenesis were investigated. Also, whether azilsartan restrains LPS-triggered TNF-α mRNA and protein expression in macrophages and RANKL expression in osteoblasts were assessed. Furthermore, western blotting for analysis of mitogen-activated protein kinases (MAPKs) signaling was conducted.ResultsAzilsartan-treated calvariae exhibited significantly lower bone resorption and osteoclastogenesis than those treated with LPS alone. In vivo, LPS with azilsartan administration resulted in lower levels of receptor activator of RANKL and TNF-α mRNA expression than LPS administration alone. Nevertheless, azilsartan did not show inhibitory effect on RANKL- and TNF-α-triggered osteoclastogenesis in vitro. Compared to macrophages treated with LPS, TNF-α mRNA and protein levels were lower in macrophages treated by LPS with azilsartan. In contrast, RANKL mRNA and protein expression levels in osteoblasts were the same in cells co-treated with azilsartan and LPS and those exposed to LPS only. Furthermore, azilsartan suppressed LPS-triggered MAPKs signaling pathway in macrophages. After 5-day supracalvarial injection, there is no difference between TNF-α injection group and TNF-α with azilsartan injection group.ConclusionThese findings imply that azilsartan prevents LPS-triggered TNF-α production in macrophages, which in turn prevents LPS-Triggered osteoclast formation and bone resorption in vivo.

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Relationship of renin‐angiotensin system polymorphisms with ambulatory and central blood pressure in patients with hypertension

Cited by 5 publications

References 27 publications

Salt-Sensitive Hypertension Induces Osteoclastogenesis and Bone Resorption via Upregulation of Angiotensin II Type 1 Receptor Expression in Osteoblasts

Salt-Sensitive Hypertension Induces Osteoclastogenesis and Bone Resorption via Upregulation of Angiotensin II Type 1 Receptor Expression in Osteoblasts

Mathematical modeling of the influence ofACE I/Dpolymorphism on blood pressure and antihypertensive therapy

Azilsartan inhibits inflammation-triggered bone resorption and osteoclastogenesis in vivo via suppression of TNF-α expression in macrophages

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