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The interacting physiology of COVID-19 and the renin-angiotensin-aldosterone system: Key agents for treatment.
Lumbers, ER, Head, R, Smith, GR, Delforce, SJ, Jarrott, B, H Martin, J, Pringle, KG
Pharmacology research & perspectives. 2022;(1):e00917
Abstract
SARS-CoV-2 interacting with its receptor, angiotensin-converting enzyme 2 (ACE2), turns the host response to viral infection into a dysregulated uncontrolled inflammatory response. This is because ACE2 limits the production of the peptide angiotensin II (Ang II) and SARS-CoV-2, through the destruction of ACE2, allows the uncontrolled production of Ang II. Recovery from trauma requires activation of both a tissue response to injury and activation of a whole-body response to maintain tissue perfusion. Tissue and circulating renin-angiotensin systems (RASs) play an essential role in the host response to infection and injury because of the actions of Ang II, mediated via its AT1 receptor. Both tissue and circulating arms of the renin angiotensin aldosterone system's (RAAS) response to injury need to be regulated. The effects of Ang II and the steroid hormone, aldosterone, on fluid and electrolyte homeostasis and on the circulation are controlled by elaborate feedback networks that respond to alterations in the composition and volume of fluids within the circulatory system. The role of Ang II in the tissue response to injury is however, controlled mainly by its metabolism and conversion to Ang-(1-7) by the enzyme ACE2. Ang-(1-7) has effects that are contrary to Ang II-AT1 R mediated effects. Thus, destruction of ACE2 by SARS-CoV-2 results in loss of control of the pro-inflammatory actions of Ang II and tissue destruction. Therefore, it is the response of the host to SARS-CoV-2 that is responsible for the pathogenesis of COVID-19.
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Evaluating the effects of sodium glucose co-transporter -2 inhibitors from a renin-angiotensin-aldosterone system perspective in patients infected with COVID-19: contextualizing findings from the dapagliflozin in respiratory failure in patients with COVID-19 study.
Moustafa, DA, Imran, Z, Ismail, R, Rayan, M, Gadeau, AP, Eldassouki, H, Abdulrahman, N, Mraiche, F
Molecular biology reports. 2022;(3):2321-2324
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Abstract
Numerous studies demonstrate parallels between CVD, type 2 diabetes mellitus (T2DM) and COVID-19 pathology, which accentuate pre-existing complications in patients infected with COVID-19 and potentially exacerbate the infection course. Antidiabetic drugs such as sodium-glucose transporter-2 (SGLT-2) inhibitors have garnered substantial attention recently due to their efficacy in reducing the severity of cardiorenal disease. The effect of SGLT-2 inhibitors in patients with COVID-19 remains unclear particularly since SGLT-2 inhibitors contribute to altering the RAAS cascade activity, which includes ACE-2, the major cell entry receptor for SARS-CoV2. A study, DARE-19, was carried out to unveil the effects of SGLT-2 inhibitor treatment on comorbid disease complications and concomitant COVID-19 outcomes and demonstrated no statistical significance. However, the need for further studies is essential to provide conclusive clinical findings.
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Effects of SGLT2 Inhibitors and GLP-1 Receptor Agonists on Renin-Angiotensin-Aldosterone System.
Puglisi, S, Rossini, A, Poli, R, Dughera, F, Pia, A, Terzolo, M, Reimondo, G
Frontiers in endocrinology. 2021;:738848
Abstract
Sodium-glucose cotransporters inhibitors (SGLT2-i) and GLP-1 receptor agonists (GLP1-RA) are glucose-lowering drugs that are proved to reduce the cardiovascular (CV) risk in type 2 diabetes mellitus (T2DM). In this process, the renin-angiotensin-aldosterone system (RAAS) is assumed to play a role. The inhibition of SGLT2 improves hyperglycemia hampering urinary reabsorption of glucose and inducing glycosuria. This "hybrid" diuretic effect, which couples natriuresis with osmotic diuresis, potentially leads to systemic RAAS activation. However, the association between SGLT2-i and systemic RAAS activation is not straightforward. Available data indicate that SGLT2-i cause plasma renin activity (PRA) increase in the early phase of treatment, while PRA and aldosterone levels remain unchanged in chronic treated patients. Furthermore, emerging studies provide evidence that SGLT2-i might have an interfering effect on aldosterone/renin ratio (ARR) in patients with T2DM, due to their diuretic and sympathoinhibition effects. The cardio- and reno-protective effects of GLP-1-RA are at least in part related to the interaction with RAAS. In particular, GLP1-RA counteract the action of angiotensin II (ANG II) inhibiting its synthesis, increasing the inactivation of its circulating form and contrasting its action on target tissue like glomerular endothelial cells and cardiomyocytes. Furthermore, GLP1-RA stimulate natriuresis inhibiting Na+/H+ exchanger NHE-3, which is conversely activated by ANG II. Moreover, GLP1 infusion acutely reduces circulating aldosterone, but this effect does not seem to be chronically maintained in patients treated with GLP1-RA. In conclusion, both SGLT2-i and GLP1-RA seem to have several effects on RAAS, though additional studies are needed to clarify this relationship.
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Transforming the Care of Patients with Diabetic Kidney Disease.
Brosius, FC, Cherney, D, Gee, PO, Harris, RC, Kliger, AS, Tuttle, KR, Quaggin, SE, ,
Clinical journal of the American Society of Nephrology : CJASN. 2021;(10):1590-1600
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Abstract
Diabetes and its associated complications pose an immediate threat to humankind. Diabetic kidney disease is one of the most devastating complications, increasing the risk of death more than ten-fold over the general population. Until very recently, the only drugs proven and recommended to slow the progression of diabetic kidney disease were angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers, which act by inhibiting the renin-angiotensin system. Despite their efficacy as kidney and cardiovascular protective therapies and as antihypertensive agents, renin-angiotensin system inhibitors have been grossly underutilized. Moreover, even when renin-angiotensin system inhibitors are used, patients still have a high residual risk of diabetic kidney disease progression. Finally, the kidney-protective effect of renin-angiotensin system inhibitors has been categorically demonstrated only in patients with macroalbuminuria included in the Irbesartan Diabetic Nephropathy Trial (IDNT) and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trials, not in other individuals. The lack of new therapies to treat diabetic kidney disease over the past 2 decades has therefore represented a tremendous challenge for patients and health care providers alike. In recent years, a number of powerful new therapies have emerged that promise to transform care of patients with diabetes and kidney disease. The challenge to the community is to ensure rapid implementation of these treatments. This white paper highlights advances in treatment, opportunities for patients, challenges, and possible solutions to advance kidney health, and introduces the launch of the Diabetic Kidney Disease Collaborative at the American Society of Nephrology, to aid in accomplishing these goals.
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Evaluating sources of bias in observational studies of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use during COVID-19: beyond confounding.
Cohen, JB, D'Agostino McGowan, L, Jensen, ET, Rigdon, J, South, AM
Journal of hypertension. 2021;(4):795-805
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Abstract
Concerns over ACE inhibitor or ARB use to treat hypertension during COVID-19 remain unresolved. Although studies using more robust methodologies provided some clarity, sources of bias persist and it remains critical to quickly address this question. In this review, we discuss pernicious sources of bias using a causal model framework, including time-varying confounder, collider, information, and time-dependent bias, in the context of recently published studies. We discuss causal inference methodologies that can address these issues, including causal diagrams, time-to-event analyses, sensitivity analyses, and marginal structural modeling. We discuss effect modification and we propose a role for causal mediation analysis to estimate indirect effects via mediating factors, especially components of the renin--angiotensin system. Thorough knowledge of these sources of bias and the appropriate methodologies to address them is crucial when evaluating observational studies to inform patient management decisions regarding whether ACE inhibitors or ARBs are associated with greater risk from COVID-19.
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Fibrinogen and a Triad of Thrombosis, Inflammation, and the Renin-Angiotensin System in Premature Coronary Artery Disease in Women: A New Insight into Sex-Related Differences in the Pathogenesis of the Disease.
Kryczka, KE, Kruk, M, Demkow, M, Lubiszewska, B
Biomolecules. 2021;(7)
Abstract
Coronary artery disease (CAD) is the leading cause of morbidity and mortality in women worldwide. Its social impact in the case of premature CAD is particularly devastating. Many differences in the presentation of the disease in women as compared to men, including atypical symptoms, microvascular involvement, and differences in pathology of plaque formation or progression, make CAD diagnosis in women a challenge. The contribution of different risk factors, such as smoking, diabetes, hyperlipidemia, or obesity, may vary between women and men. Certain pathological pathways may have different sex-related magnitudes on CAD formation and progression. In spite of the already known differences, we lack sufficiently powered studies, both clinical and experimental, that assess the multipathogenic differences in CAD formation and progression related to sex in different age periods. A growing quantity of data that are presented in this article suggest that thrombosis with fibrinogen is of more concern in the case of premature CAD in women than are other coagulation factors, such as factors VII and VIII, tissue-type plasminogen activator, and plasminogen inhibitor-1. The rise in fibrinogen levels in inflammation is mainly affected by interleukin-6 (IL-6). The renin-angiotensin (RA) system affects the inflammatory process by increasing the IL-6 level. Unlike in men, in young women, the hypertensive arm of the RA system is naturally downregulated by estrogens. At the same time, estrogens promote the fibrinolytic path of the RA system. In young women, the promoted fibrinolytic process upregulates IL-6 release from leukocytes via fibrin degradation products. Moreover, fibrinogen, whose higher levels are observed in women, increases IL-6 synthesis and exacerbates inflammation, contributing to CAD. Therefore, the synergistic interplay between thrombosis, inflammation, and the RA system appears to have a more significant influence on the underlying CAD atherosclerotic plaque formation in young women than in men. This issue is further discussed in this review. Fibrinogen is the biomolecule that is central to these three pathways. In this review, fibrinogen is shown as the biomolecule that possesses a different impact on CAD formation, progression, and destabilization in women to that observed in men, being more pathogenic in women at the early stages of the disease than in men. Fibrinogen is a three-chain glycoprotein involved in thrombosis. Although the role of thrombosis is of great magnitude in acute coronary events, fibrinogen also induces atherosclerosis formation by accumulating in the arterial wall and enabling low-density lipoprotein cholesterol aggregation. Its level rises during inflammation and is associated with most cardiovascular risk factors, particularly smoking and diabetes. It was noted that fibrinogen levels were higher in women than in men as well as in the case of premature CAD in women. The causes of this phenomenon are not well understood. The higher fibrinogen levels were found to be associated with a greater extent of coronary atherosclerosis in women with CAD but not in men. Moreover, the lysability of a fibrin clot, which is dependent on fibrinogen properties, was reduced in women with subclinical CAD compared to men at the same stage of the disease, as well as in comparison to women without coronary artery atherosclerosis. These findings suggest that the magnitude of the pathological pathways contributing to premature CAD differs in women and men, and they are discussed in this review. While many gaps in both experimental and clinical studies on sex-related differences in premature CAD exist, further studies on pathological pathways are needed.
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The Renin-Angiotensin System: A Key Role in SARS-CoV-2-Induced COVID-19.
El-Arif, G, Farhat, A, Khazaal, S, Annweiler, C, Kovacic, H, Wu, Y, Cao, Z, Fajloun, Z, Khattar, ZA, Sabatier, JM
Molecules (Basel, Switzerland). 2021;(22)
Abstract
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), was first identified in Eastern Asia (Wuhan, China) in December 2019. The virus then spread to Europe and across all continents where it has led to higher mortality and morbidity, and was declared as a pandemic by the World Health Organization (WHO) in March 2020. Recently, different vaccines have been produced and seem to be more or less effective in protecting from COVID-19. The renin-angiotensin system (RAS), an essential enzymatic cascade involved in maintaining blood pressure and electrolyte balance, is involved in the pathogenicity of COVID-19, since the angiotensin-converting enzyme II (ACE2) acts as the cellular receptor for SARS-CoV-2 in many human tissues and organs. In fact, the viral entrance promotes a downregulation of ACE2 followed by RAS balance dysregulation and an overactivation of the angiotensin II (Ang II)-angiotensin II type I receptor (AT1R) axis, which is characterized by a strong vasoconstriction and the induction of the profibrotic, proapoptotic and proinflammatory signalizations in the lungs and other organs. This mechanism features a massive cytokine storm, hypercoagulation, an acute respiratory distress syndrome (ARDS) and subsequent multiple organ damage. While all individuals are vulnerable to SARS-CoV-2, the disease outcome and severity differ among people and countries and depend on a dual interaction between the virus and the affected host. Many studies have already pointed out the importance of host genetic polymorphisms (especially in the RAS) as well as other related factors such age, gender, lifestyle and habits and underlying pathologies or comorbidities (diabetes and cardiovascular diseases) that could render individuals at higher risk of infection and pathogenicity. In this review, we explore the correlation between all these risk factors as well as how and why they could account for severe post-COVID-19 complications.
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Novelties in Therapy of Chronic Heart Failure.
Doimo, S, Pavan, D
Heart failure clinics. 2021;(2):255-262
Abstract
In recent decades, considerable advances have been made in the treatment of heart failure. The main target of heart failure therapy is the inhibition of the sympathetic nervous system and renin-angiotensin-aldosterone system. The angiotensin receptor blockers represent a breakthrough in the treatment of heart failure with a demonstrated effect on reduction of cardiovascular events. However, new perspectives derive from latest drugs developed for diabetes, iron deficiency, and hyperkalemia. New frontiers are also opened to the development of neurohormonal therapies, antagonists of inflammatory mediators, inotropic agents, and cell-based treatments.
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The evolving complexity of the collecting duct renin-angiotensin system in hypertension.
Prieto, MC, Gonzalez, AA, Visniauskas, B, Navar, LG
Nature reviews. Nephrology. 2021;(7):481-492
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Abstract
The intrarenal renin-angiotensin system is critical for the regulation of tubule sodium reabsorption, renal haemodynamics and blood pressure. The excretion of renin in urine can result from its increased filtration, the inhibition of renin reabsorption by megalin in the proximal tubule, or its secretion by the principal cells of the collecting duct. Modest increases in circulating or intrarenal angiotensin II (ANGII) stimulate the synthesis and secretion of angiotensinogen in the proximal tubule, which provides sufficient substrate for collecting duct-derived renin to form angiotensin I (ANGI). In models of ANGII-dependent hypertension, ANGII suppresses plasma renin, suggesting that urinary renin is not likely to be the result of increased filtered load. In the collecting duct, ANGII stimulates the synthesis and secretion of prorenin and renin through the activation of ANGII type 1 receptor (AT1R) expressed primarily by principal cells. The stimulation of collecting duct-derived renin is enhanced by paracrine factors including vasopressin, prostaglandin E2 and bradykinin. Furthermore, binding of prorenin and renin to the prorenin receptor in the collecting duct evokes a number of responses, including the non-proteolytic enzymatic activation of prorenin to produce ANGI from proximal tubule-derived angiotensinogen, which is then converted into ANGII by luminal angiotensin-converting enzyme; stimulation of the epithelial sodium channel (ENaC) in principal cells; and activation of intracellular pathways linked to the upregulation of cyclooxygenase 2 and profibrotic genes. These findings suggest that dysregulation of the renin-angiotensin system in the collecting duct contributes to the development of hypertension by enhancing sodium reabsorption and the progression of kidney injury.
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Breast cancer and the renin-angiotensin system (RAS): Therapeutic approaches and related metabolic diseases.
de Miranda, FS, Guimarães, JPT, Menikdiwela, KR, Mabry, B, Dhakal, R, Rahman, RL, Moussa, H, Moustaid-Moussa, N
Molecular and cellular endocrinology. 2021;:111245
Abstract
The Renin-Angiotensin System (RAS) is classically recognized for regulating blood pressure and fluid balance. Recently, this role has extended to other areas including inflammation, obesity, diabetes, as well as breast cancer. RAS components are expressed in normal and cancerous breast tissues, and downregulation of RAS inhibits metastasis, proliferation, angiogenesis, and desmoplasia in the tumor microenvironment. Therefore, RAS inhibitors (Angiotensin receptor blockers, ARBs, or angiotensin converting enzyme inhibitors, ACE-I) may be beneficial as preventive adjuvant therapies to thwart breast cancer development and improve outcomes, respectively. Given the beneficial effects of RAS inhibitors in metabolic diseases, which often co-exist in breast cancer patients, combining RAS inhibitors with other breast cancer therapies may enhance the effectiveness of current treatments. This review scrutinizes above associations, to advance our understanding of the role of RAS in breast cancer and its potential for repurposing of RAS inhibitors to improve the therapeutic approach for breast cancer patients.