Chronic inflammation and atherosclerosis : A critical role for renin angiotensin system that is activated by lifestyle-related diseases

A new form of severe acute respiratory syndrome (SARS) caused by SARS-coronavirus 2 (CoV-2), called COVID-19, has become a global threat in 2020. The mortality rate from COVID-19 is high in hypertensive patients, making this association especially dangerous. There appears to be a consensus, despite the lack of experimental data, that angiotensin II (ANG II) is linked to the pathogenesis of COVID-19. This process may occur due to acquired deficiency of angiotensin-converting enzyme 2 (ACE2), resulting in reduced degradation of ANG II. Furthermore, ANG II has a critical role in the genesis and worsening of hypertension. In this context, the idea that there is a surge in the level of ANG II with COVID-19 infection, causing multiple organ injuries in hypertensive patients becomes attractive. However, the role of other components of the renin angiotensin system (RAS) in this scenario requires elucidation. The identification of other RAS components in COVID-19 hypertension may provide both diagnostic and therapeutic benefits. Here, we summarize the pathophysiologic contributions of different components of RAS in hypertension and their possible correlation with poor outcome observed in hypertensive patients with COVID-19.

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Review: Sex specific programming: A critical role for the renal renin–angiotensin system

Placenta ◽

10.1016/j.placenta.2010.01.006 ◽

2010 ◽

Vol 31 ◽

pp. S40-S46 ◽

Cited By ~ 74

Author(s):

K.M. Moritz ◽

J.S.M. Cuffe ◽

L.B. Wilson ◽

H. Dickinson ◽

M.E. Wlodek ◽

...

Keyword(s):

Critical Role ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Renin Angiotensin

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The Renin–Angiotensin System in the Tumor Microenvironment of Glioblastoma

Cancers ◽

10.3390/cancers13164004 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4004

Author(s):

Michael O’Rawe ◽

Ethan J. Kilmister ◽

Theo Mantamadiotis ◽

Andrew H. Kaye ◽

Swee T. Tan ◽

...

Keyword(s):

Tumor Microenvironment ◽

Critical Role ◽

Tumor Development ◽

Renin Angiotensin System ◽

Cost Effective ◽

Therapy Resistance ◽

Current Standard ◽

Angiotensin System ◽

Renin Angiotensin ◽

Therapeutic Alternative

Glioblastoma (GB) is an aggressive primary brain tumor. Despite intensive research over the past 50 years, little advance has been made to improve the poor outcome, with an overall median survival of 14.6 months following standard treatment. Local recurrence is inevitable due to the quiescent cancer stem cells (CSCs) in GB that co-express stemness-associated markers and components of the renin–angiotensin system (RAS). The dynamic and heterogeneous tumor microenvironment (TME) plays a fundamental role in tumor development, progression, invasiveness, and therapy resistance. There is increasing evidence showing the critical role of the RAS in the TME influencing CSCs via its upstream and downstream pathways. Drugs that alter the hallmarks of cancer by modulating the RAS present a potential new therapeutic alternative or adjunct to conventional treatment of GB. Cerebral and GB organoids may offer a cost-effective method for evaluating the efficacy of RAS-modulating drugs on GB. We review the nexus between the GB TME, CSC niche, and the RAS, and propose re-purposed RAS-modulating drugs as a potential therapeutic alternative or adjunct to current standard therapy for GB.

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The Potential Therapeutic Value of Renin-Angiotensin System Inhibitors in the Treatment of Colorectal Cancer

Current Pharmaceutical Design ◽

10.2174/1381612827666211011113308 ◽

2021 ◽

Vol 27 ◽

Author(s):

Ehsan Tabatabai ◽

Majid Khazaei ◽

Mohammad Reza Parizadeh ◽

Mohammad Nouri ◽

Seyed Mahdi Hassanian ◽

...

Keyword(s):

Colorectal Cancer ◽

Therapeutic Potential ◽

Critical Role ◽

Renin Angiotensin System ◽

Angiotensin Converting Enzyme Inhibitors ◽

Angiotensin Ii Receptor ◽

Converting Enzyme Inhibitors ◽

Angiotensin System ◽

Renin Angiotensin ◽

Promote Cell Proliferation

: Colorectal cancer is the third most common cancer globally. Despite extensive preclinical and clinical studies, it is still among the leading causes of cancer-related death, and a need for new therapeutic options is required. The renin-angiotensin system plays an important role in regulating blood pressure and cell growth. In addition to their hemodynamic effects, some of the renin-angiotensin system components, such as angiotensin, are also growth factors that promote cell proliferation and angiogenesis, and its dysregulation is reported to be associated with poor prognosis in colorectal cancer. Here we describe the critical role of the renin-angiotensin system pathway in colorectal cancer as well as the preclinical and clinical investigations renin-angiotensin system inhibitors: angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers as a potential therapeutic target in the treatment of colorectal cancer. Several studies have been shown that the inhibition of these pathways can reduce tumor growth and metastasis; however, some of the data remain inconsistent. There is accumulating evidence of the therapeutic potential of some inhibitors, such as Losartan which are now in clinical phases in the treatment of several malignancies using Nivolumab in combination with FOLFIRINOX in pancreatic cancer. Further investigations are warranted to improve the efficacy and selectivity of current and future anticancer strategies targeting renin-angiotensin systems.

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Renin–Angiotensin–Aldosterone System and Immunomodulation: A State-of-the-Art Review

Cells ◽

10.3390/cells10071767 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1767

Author(s):

Driss Laghlam ◽

Mathieu Jozwiak ◽

Lee S. Nguyen

Keyword(s):

Critical Role ◽

Solid Organ Transplantation ◽

Specific Treatment ◽

Renin Angiotensin System ◽

Solid Organ ◽

Angiotensin System ◽

Renin Angiotensin ◽

Regional Specificity ◽

Ras Blockers ◽

The Subject

The renin–angiotensin system (RAS) has long been described in the field of cardiovascular physiology as the main player in blood pressure homeostasis. However, other effects have since been described, and include proliferation, fibrosis, and inflammation. To illustrate the immunomodulatory properties of the RAS, we chose three distinct fields in which RAS may play a critical role and be the subject of specific treatments. In oncology, RAS hyperactivation has been associated with tumor migration, survival, cell proliferation, and angiogenesis; preliminary data showed promise of the benefit of RAS blockers in patients treated for certain types of cancer. In intensive care medicine, vasoplegic shock has been associated with severe macro- and microcirculatory imbalance. A relative insufficiency in angiotensin II (AngII) was associated to lethal outcomes and synthetic AngII has been suggested as a specific treatment in these cases. Finally, in solid organ transplantation, both AngI and AngII have been associated with increased rejection events, with a regional specificity in the RAS activity. These elements emphasize the complexity of the direct and indirect interactions of RAS with immunomodulatory pathways and warrant further research in the field.

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A critical role of cardiac fibroblast-derived exosomes in activating renin angiotensin system in cardiomyocytes

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2015.10.022 ◽

2015 ◽

Vol 89 ◽

pp. 268-279 ◽

Cited By ~ 77

Author(s):

Linmao Lyu ◽

Hui Wang ◽

Bin Li ◽

Qingyun Qin ◽

Lei Qi ◽

...

Keyword(s):

Critical Role ◽

Renin Angiotensin System ◽

Cardiac Fibroblast ◽

Angiotensin System ◽

Renin Angiotensin

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Retinal Protein O-GlcNAcylation and the Ocular Renin Angiotensin System: Signaling Cross-Roads in Diabetic Retinopathy

Current Diabetes Reviews ◽

10.2174/1573399817999210111205933 ◽

2021 ◽

Vol 17 ◽

Author(s):

Michael D. Dennis ◽

Sadie K. Dierschke

Keyword(s):

Diabetic Retinopathy ◽

Critical Role ◽

Costimulatory Molecule ◽

Renin Angiotensin System ◽

Mrna Translation ◽

Hexosamine Biosynthetic Pathway ◽

Angiotensin System ◽

Renin Angiotensin ◽

Translational Repressor ◽

The Impact

Abstract:: It is well established that diabetes and its associated hyperglycemia negatively impacts retinal function, yet we know little about the role played by augmented flux through the hexosamine biosynthetic pathway (HBP). This offshoot of the glycolytic pathway produces UDP-N-acetyl-glucosamine which serves as the substrate for post-translational Olinked modification of proteins in a process referred to as O-GlcNAcylation. HBP flux and subsequent protein OGlcNAcylation serve as a nutrient sensor, enabling cells to integrate metabolic information to appropriately modulate fundamental cellular processes including gene expression. Here we summarize the impact of diabetes on retinal physiology, highlighting recent studies that explore the role of O-GlcNAcylation-induced variation in mRNA translation in retinal dysfunction and the pathogenesis of diabetic retinopathy (DR). Augmented O-GlcNAcylation results in widespread variation in the selection of mRNAs for translation, in part, due to O-GlcNAcylation of the translational repressor 4E-BP1. Recent studies demonstrate that 4E-BP1 plays a critical role in regulating O-GlcNAcylation-induced changes in translation of the mRNAs encoding vascular endothelial growth factor (VEGF), a number of important mitochondrial proteins, and CD40, a key costimulatory molecule involved in diabetes-induced retinal inflammation. Remarkably, 4E-BP1/2 ablation delays the onset of diabetes-induced visual dysfunction in mice. Thus, pharmacological interventions to prevent the impact of O-GlcNAcylation on 4E-BP1 may represent promising therapeutics to address the development and progression of DR. In this regard, we discuss the potential interplay between retinal O-GlcNAcylation and the ocular renin-angiotensin system as a potential therapeutic target of future interventions.

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In Vivo Renin Activity Imaging in the Kidney of Progeroid Ercc1 Mutant Mice

International Journal of Molecular Sciences ◽

10.3390/ijms222212433 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12433

Author(s):

Bibi S. van Thiel ◽

Janette van der Linden ◽

Yanto Ridwan ◽

Ingrid M. Garrelds ◽

Marcel Vermeij ◽

...

Keyword(s):

Near Infrared ◽

Critical Role ◽

Renin Angiotensin System ◽

Renin Activity ◽

Ras Signaling ◽

Angiotensin System ◽

Renin Angiotensin ◽

Virtual Absence ◽

Age Related

Changes in the renin–angiotensin system, known for its critical role in the regulation of blood pressure and sodium homeostasis, may contribute to aging and age-related diseases. While the renin–angiotensin system is suppressed during aging, little is known about its regulation and activity within tissues. However, this knowledge is required to successively treat or prevent renal disease in the elderly. Ercc1 is involved in important DNA repair pathways, and when mutated causes accelerated aging phenotypes in humans and mice. In this study, we hypothesized that unrepaired DNA damage contributes to accelerated kidney failure. We tested the use of the renin-activatable near-infrared fluorescent probe ReninSense680™ in progeroid Ercc1d/− mice and compared renin activity levels in vivo to wild-type mice. First, we validated the specificity of the probe by detecting increased intrarenal activity after losartan treatment and the virtual absence of fluorescence in renin knock-out mice. Second, age-related kidney pathology, tubular anisokaryosis, glomerulosclerosis and increased apoptosis were confirmed in the kidneys of 24-week-old Ercc1d/− mice, while initial renal development was normal. Next, we examined the in vivo renin activity in these Ercc1d/− mice. Interestingly, increased intrarenal renin activity was detected by ReninSense in Ercc1d/− compared to WT mice, while their plasma renin concentrations were lower. Hence, this study demonstrates that intrarenal RAS activity does not necessarily run in parallel with circulating renin in the aging mouse. In addition, our study supports the use of this probe for longitudinal imaging of altered RAS signaling in aging.

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