Autophagy in metabolic syndrome: breaking the wheel by targeting the renin–angiotensin system

Menikdiwela, Kalhara R.; Ramalingam, Latha; Rasha, Fahmida; Wang, Shu; Dufour, Jannette M.; Kalupahana, Nishan S.; Sunahara, Karen K. S.; Martins, Joilson O.; Moustaid‐Moussa, Naima

doi:10.1038/s41419-020-2275-9

Cited by 66 publications

(62 citation statements)

References 173 publications

(291 reference statements)

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“…However, additional local functions of RAAS have also been identified in several metabolic tissues, including adipose tissue and the pancreas. 11,29 Components of RAAS (AT1, AT2, Agt, Ang II and ACE) are expressed in murine and human pancreatic islets with a local role within the pancreas. 17,[30][31][32] RAAS regulates islet blood flow; 33 however, specific non-hemodynamic functions in pancreatic beta cells are not well established.…”

Section: Discussionmentioning

confidence: 99%

<p>Endoplasmic Reticulum (ER) Stress in Part Mediates Effects of Angiotensin II in Pancreatic Beta Cells</p>

Ramalingam¹,

Sopontammarak²,

Menikdiwela³

et al. 2020

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Introduction: The renin angiotensin aldosterone system (RAAS) is a hormone system known for its role in regulating blood pressure and fluid balance. Numerous RAAS inhibitors routinely prescribed for hypertension have also beneficial effects in type 2 diabetes (T2D) prevention. RAAS components are expressed locally in many tissues, including adipose tissue and pancreas, where they exert metabolic effects through RAAS bioactive hormone angiotensin II (Ang II). Pancreatic beta cells are specialized insulin-producing cells; they have also developed endoplasmic reticulum (ER), which contributes to beta cell dysfunction, when proteins are misfolded in disease states such as T2D. However, no studies have investigated the relationship between RAAS and ER stress in beta cells as a mechanism linking pancreatic RAAS to T2D. Hence, we hypothesized that Ang II treatment of beta cells increases ER stress and inflammation leading to reduced insulin secretion. Methods: To test this hypothesis, we treated clonal INS-1E beta cells and human islets with Ang II and assessed changes in ER stress markers. INS-1E beta cells were also used for measuring insulin secretion and for assessing the effects of various RAAS and ER stress inhibitors. Results: We demonstrated that Ang II significantly increased the expression of ER stress genes such as Chop and Atf4 and reduced insulin secretion. Furthermore, inhibition of Ang II production with an angiotensin converting enzyme inhibitor (ACEi, captopril) significantly reduced ER stress. Moreover, the Ang II receptor blockade reduced ER stress significantly and rescued insulin secretion. Discussion: This research provides new mechanistic insight into the role of RAAS activation via ER stress on beta cell dysfunction and provides additional evidence for protective effects of RAAS inhibition in T2D.

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Section: Discussionmentioning

confidence: 99%

<p>Endoplasmic Reticulum (ER) Stress in Part Mediates Effects of Angiotensin II in Pancreatic Beta Cells</p>

Ramalingam¹,

Sopontammarak²,

Menikdiwela³

et al. 2020

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“…Dysfunction and dysregulation in autophagy are related to obesity [147][148][149], age, and male sex [150] in many diseases. In particular, obese people present an increased number of autophagosomes due to the combination of increased inflammation with inhibition of the last steps of autophagy [147,148].…”

Section: Autophagy Immunity and Virus Infectionmentioning

confidence: 99%

Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment

Cicco

Racanelli

et al. 2020

Mediators of Inflammation

153

148

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COVID-19 is a pandemic disease caused by the new coronavirus SARS-CoV-2 that mostly affects the respiratory system. The consequent inflammation is not able to clear viruses. The persistent excessive inflammatory response can build up a clinical picture that is very difficult to manage and potentially fatal. Modulating the immune response plays a key role in fighting the disease. One of the main defence systems is the activation of neutrophils that release neutrophil extracellular traps (NETs) under the stimulus of autophagy. Various molecules can induce NETosis and autophagy; some potent activators are damage-associated molecular patterns (DAMPs) and, in particular, the high-mobility group box 1 (HMGB1). This molecule is released by damaged lung cells and can induce a robust innate immunity response. The increase in HMGB1 and NETosis could lead to sustained inflammation due to SARS-CoV-2 infection. Therefore, blocking these molecules might be useful in COVID-19 treatment and should be further studied in the context of targeted therapy.

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“…Ang-II activation of angiotensin type 2 receptor (AT2R) attenuates autophagy, whereas Ang-II activation of AT1R induces autophagy through AMPK/mTOR signaling. Ang-1-7 induces autophagy via the cofilin receptor (26). Activation of intestinal RAS promotes Paneth cell autophagy leading to bowel inflammation and arrested release of antimicrobial factors including defensin 5, which inhibits SARS-CoV-2 infection by cloaking ACE2 (27).…”

Section: Ras Modulates Autophagymentioning

confidence: 99%

SARS-CoV-2 Infections and ACE2: Clinical Outcomes Linked With Increased Morbidity and Mortality in Individuals With Diabetes

et al. 2020

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Individuals with diabetes suffering from coronavirus disease 2019 (COVID-19) exhibit increased morbidity and mortality compared with individuals without diabetes. In this Perspective, we critically evaluate and argue that this is due to a dysregulated renin-angiotensin system (RAS). Previously, we have shown that loss of angiotensin-I converting enzyme 2 (ACE2) promotes the ACE/angiotensin-II (Ang-II)/angiotensin type 1 receptor (AT1R) axis, a deleterious arm of RAS, unleashing its detrimental effects in diabetes. As suggested by the recent reports regarding the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), upon entry into the host, this virus binds to the extracellular domain of ACE2 in nasal, lung, and gut epithelial cells through its spike glycoprotein subunit S1. We put forth the hypothesis that during this process, reduced ACE2 could result in clinical deterioration in COVID-19 patients with diabetes via aggravating Ang-II-dependent pathways and partly driving not only lung but also bone marrow and gastrointestinal pathology. In addition to systemic RAS, the pathophysiological response of the local RAS within the intestinal epithelium involves mechanisms distinct from that of RAS in the lung; however, both lung and gut are impacted by diabetes-induced bone marrow dysfunction. Careful targeting of the systemic and tissue RAS may optimize clinical outcomes in subjects with diabetes infected with SARS-CoV-2. This Perspective focuses on providing an overview of recent studies describing the impact of the coronavirus disease 2019 (COVID-19) pandemic on individuals with diabetes and several possible mechanisms for why individuals with diabetes represent a particularly at-risk population. In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the pathogen responsible for the outbreak that began in Wuhan, China, and rapidly spread throughout China, Europe, and the U.S. Currently, the SARS-CoV-2 virus has infected more than 12 million individuals worldwide, with more than 555,000 COVID-19 cases resulting in death, and the number of individuals becoming infected is increasing. Thus far, SARS-CoV-2 mechanisms of infectivity remain incompletely understood. Some insight, however, has been provided by the previous pandemic of SARS-CoV in 2002, but the brutality of COVID-19 has raised many unanswered questions and the pace of science needs to increase. Here, we put forth the argument that a dysregulated renin-angiotensin system (RAS), typically seen in individuals with diabetes, increases the risk of a poor clinical outcome following COVID-19 infection. Clinical Burden of COVID-19 in Patients With Diabetes Conditions associated with increased morbidity and mortality in individuals infected with SARS-CoV-2 are the presence of diabetes, hypertension, cardiovascular disease, and severe obesity (BMI $40 kg/m 2) (1-3). Considering the high prevalence of hypertension, cardiovascular disease, and obesity in individuals with diabetes, it is difficult to know...

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Autophagy in metabolic syndrome: breaking the wheel by targeting the renin–angiotensin system

Cited by 66 publications

References 173 publications

<p>Endoplasmic Reticulum (ER) Stress in Part Mediates Effects of Angiotensin II in Pancreatic Beta Cells</p>

<p>Endoplasmic Reticulum (ER) Stress in Part Mediates Effects of Angiotensin II in Pancreatic Beta Cells</p>

Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment

SARS-CoV-2 Infections and ACE2: Clinical Outcomes Linked With Increased Morbidity and Mortality in Individuals With Diabetes

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