The potential therapeutic use of renin–angiotensin system inhibitors in the treatment of inflammatory diseases

Ranjbar, Reza; Shafiee, Mojtaba; Hesari, AmirReza; Ferns, Gordon A.; Ghasemi, Faezeh; Rezayi, Majid

doi:10.1002/jcp.27205

Cited by 54 publications

(36 citation statements)

References 149 publications

(308 reference statements)

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“…For example, when the renal blood flow is reduced, the kidneys' juxtaglomerular cells secrete renin directly into the blood circulation. This secreted renin converts angiotensinogen released by the liver to be angiotensin1 (Ang1), which is then converted to be angiotensin2 (Ang2) by ACE in pulmonary vascular endothelial cells [117,118,123]. Ang2 plays a central role in the RAS by acting on the angiotensin type 2 receptors AT1R and AT2R.…”

Section: The Physiology Of the Renin-angiotensin System And Ace2mentioning

confidence: 99%

Inflammation Triggered by SARS-CoV-2 and ACE2 Augment Drives Multiple Organ Failure of Severe COVID-19: Molecular Mechanisms and Implications

et al. 2020

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The widespread occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a pandemic of coronavirus disease 2019 (COVID-19). The S spike protein of SARS-CoV-2 binds with angiotensin-converting enzyme 2 (ACE2) as a functional “receptor” and then enters into host cells to replicate and damage host cells and organs. ACE2 plays a pivotal role in the inflammation, and its downregulation may aggravate COVID-19 via the renin-angiotensin system, including by promoting pathological changes in lung injury and involving inflammatory responses. Severe patients of COVID-19 often develop acute respiratory distress syndrome and multiple organ dysfunction/failure with high mortality that may be closely related to the hyper-proinflammatory status called the “cytokine storm.” Massive cytokines including interleukin-6, nuclear factor kappa B (NFκB), and tumor necrosis factor alpha (TNFα) released from SARS-CoV-2-infected macrophages and monocytes lead inflammation-derived injurious cascades causing multi-organ injury/failure. This review summarizes the current evidence and understanding of the underlying mechanisms of SARS-CoV-2, ACE2 and inflammation co-mediated multi-organ injury or failure in COVID-19 patients.

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Section: The Physiology Of the Renin-angiotensin System And Ace2mentioning

confidence: 99%

Inflammation Triggered by SARS-CoV-2 and ACE2 Augment Drives Multiple Organ Failure of Severe COVID-19: Molecular Mechanisms and Implications

et al. 2020

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“…A previous study has reported an RAS alternation in neural differentiation and several pathologic conditions such as MS [10,11]. e idea of measuring serum ACE levels in ON is associated with studies investigating the role played by RAS axis and angiotensin in autoimmune and inflammatory diseases [12][13][14][15]. In some studies, RAS and related factors such as angiotensin I, angiotensin II, and serum ACE were claimed to be one of the key elements affecting and regulating inflammatory responses in the brain [16].…”

Section: Introductionmentioning

confidence: 99%

Serum Level of the Angiotensin-Converting Enzyme in Patients with Idiopathic Acute Optic Neuritis: A Case-Control Study

et al. 2020

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Purpose. To evaluate the serum level of angiotensin-converting enzyme (ACE) as an important component of the renin-angiotensin system (RAS) in optic neuritis (ON) compared to the healthy control group in the context investigating the possible role of ACE in ON pathogenesis. Methods. This case-control study was conducted on patients with ON and healthy controls. Serum ACE levels were assessed and compared between the two groups by using commercially available kits by ELISA for ACE. Results. Sixty-five ON patients (75.4% female, mean age 29.70 ± 8.30 years) and 65 controls (75.4% female, mean age 29.66 ± 8.36 years) were enrolled. The median serum ACE levels were 33.5 U/L (range: 25–540) and 26 U/L (range: 22.3–72) for the ON patients and controls, respectively. Serum ACE levels were significantly higher in the patients than in the control group (P<0.001). High level of serum ACE (defined as a serum ACE >65 U/L) was present in 9 (13.8%) patients with ON and 2 (3.1%) controls. Conclusion. Our results indicated that the serum level of ACE appeared to be significantly higher in acute ON than in normal controls.

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“…The most widely used antihypertensive drug classes, angiotensin‐converting enzyme inhibitors and Ang‐II receptor blockers (ARBs), are used to treat inflammatory diseases through actions independent of their effects on blood pressure (Ranjbar et al ). Of notice, AT1R are up‐regulated in inflamed tissues.…”

mentioning

confidence: 99%

Cutaneous inflammation differentially regulates the expression and function of Angiotensin‐II types 1 and 2 receptors in rat primary sensory neurons

Benitez

Seltzer

Messina

et al. 2019

Journal of Neurochemistry

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Neuropathic and inflammatory pain results from cellular and molecular changes in dorsal root ganglion (DRG) neurons. The type‐2 receptor for Angiotensin‐II (AT2R) has been involved in this type of pain. However, the underlying mechanisms are poorly understood, including the role of the type‐1 receptor for Angiotensin‐II (AT1R). Here, we used a combination of immunohistochemistry and immunocytochemistry, RT‐PCR and in vitro and in vivo pharmacological manipulation to examine how cutaneous inflammation affected the expression of AT1R and AT2R in subpopulations of rat DRG neurons and studied their impact on inflammation‐induced neuritogenesis. We demonstrated that AT2R‐neurons express C‐ or A‐neuron markers, primarily IB4, trkA, and substance‐P. AT1R expression was highest in small neurons and co‐localized significantly with AT2R. In vitro, an inflammatory soup caused significant elevation of AT2R mRNA, whereas AT1R mRNA levels remained unchanged. In vivo, we found a unique pattern of change in the expression of AT1R and AT2R after cutaneous inflammation. AT2R increased in small neurons at 1 day and in medium size neurons at 4 days. Interestingly, cutaneous inflammation increased AT1R levels only in large neurons at 4 days. We found that in vitro and in vivo AT1R and AT2R acted co‐operatively to regulate DRG neurite outgrowth. In vivo, AT2R inhibition impacted more on non‐peptidergic C‐neurons neuritogenesis, whereas AT1R blockade affected primarily peptidergic nerve terminals. Thus, cutaneous‐induced inflammation regulated AT1R and AT2R expression and function in different DRG neuronal subpopulations at different times. These findings must be considered when targeting AT1R and AT2R to treat chronic inflammatory pain. Cover Image for this issue: doi: .

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The potential therapeutic use of renin–angiotensin system inhibitors in the treatment of inflammatory diseases

Cited by 54 publications

References 149 publications

Inflammation Triggered by SARS-CoV-2 and ACE2 Augment Drives Multiple Organ Failure of Severe COVID-19: Molecular Mechanisms and Implications

Inflammation Triggered by SARS-CoV-2 and ACE2 Augment Drives Multiple Organ Failure of Severe COVID-19: Molecular Mechanisms and Implications

Serum Level of the Angiotensin-Converting Enzyme in Patients with Idiopathic Acute Optic Neuritis: A Case-Control Study

Cutaneous inflammation differentially regulates the expression and function of Angiotensin‐II types 1 and 2 receptors in rat primary sensory neurons

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