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
SARS-CoV-2 Modulation of Insulin and Glucose Intestinal ACE2:B0AT1 dimer of heterodimers promotes enterocyte Na+-coupled uptake of phenylalanine, glutamine, tryptophan and its microbiome-generated metabolites, and other neutral amino acid agonists of nutrient-sensing receptors. These stimulate release of GLP-1 and GIP into the blood from gut mucosal enteroendocrine L cells. These incretins circulate to activate pancreatic β-cells, suppress α-cells, and afford brain satiety. SARS-CoV-2 infection of gut mucosa results in endocytosis of apical ACE2, thereby downregulating its activity, resulting in gut luminal accumulation of AT1R agonist peptides and disrupting all functions of B0AT1.
Gut–Bone Marrow Connection in Individuals With Diabetes Infected With COVID-19 The dysregulated RAS in the bone marrow with its accompanying myeloidosis promotes chronic inflammation that can contribute to both lung and gut pathology. An extensive literature supports the concept of communication between the gut and bone marrow. The gut microbiota is a critical extrinsic regulator of hematopoiesis, as very low concentrations of microbial antigens set the size of the bone marrow myeloid cell pool, and the size of this pool correlates strongly with the complexity of the intestinal microbiota. In turn, bone marrow cells migrate to the gut and impact gut function via changes in blood flow, gut immunity, and epithelial and endothelial tight junction integrity. Recruitment of bone marrow–derived immune cell to the gut is necessary for host defense and contributes to inflammation resolution and tissue healing. Loss of ACE2 in diabetes results in phylogenetic differences in the gut bacterial community composition with increases in bacteria that have been associated with peptidoglycan generation, which promotes systemic inflammation. Overactivation of bone marrow–derived immune cells including proinflammatory monocytes results in secretion of a large number of harmful cytokines into the circulation that promotes insulin resistance. In the patient with diabetes infected with COVID-19, developing pneumonia can be devastating, as preexisting systemic inflammation can rapidly lead to multiple organ failure. Inflammatory cytokine storm is a notable cause of death in critically ill COVID-19 patients and may be driven as much by gut-induced inflammation as lung injury. Thus, imbalance in the bone marrow RAS system may represent a central mechanism to not only initiate but also propagate lung and gut injury.
Possible Therapeutics That Modulate RAS From the perspective of gut enterocyte local RAS, orally delivered ACE inhibitors upregulate expression of both intestinal ACE2 and B0AT1 with their attending nutrient-signaled release of GLP-1, GIP, and mucosal antimicrobial peptides. In a preclinical colitis model, the ARB irbesartan restored intestinal B0AT1 and ACE2 expression and tryptophan homeostasis with concurrent reduction of intestinal inflammasome activity through an mTOR S6 kinase pathway. Irbesartan further shifted the gut microbiota composition toward favorable taxa and away from stress-related dysbiosis. Activation of enterocyte AT1R signaled apoptosis with reduced mucosal villus height, while losartan-mediated blockage of gut AT1R resulted in increased mucosal cell proliferation and reduced apoptosis. Increasing gut ACE2 by engineering probiotic species such as Lactobacillus paracasei (LP) to express this recombinant protein was a strategy used to prevent microvascular complications in diabetic mice. LP expressing the secretable ACE2 fused with the nontoxic subunit B of cholera toxin (which acts as a carrier to facilitate transmucosal transport), showed increased ACE2 activities in serum and tissues, and reduced diabetic complications. These results provide proof of concept for feasibility of using engineered probiotic species as a live vector for delivery of decoy hACE2 for possible treatment of enteric COVID-19 infection. rhACE2 given as intravenous medication may be explored as beneficial to COVID-19 patients with pulmonary complication, as it increases pulmonary blood flow and oxygenation in a pig model of lipopolysaccharide-induced ARDS. Supplementation with ACE2 or inhibition of Ang-II improves outcomes in acute lung injury. A pilot trial demonstrated that rhACE2 is well-tolerated in ARDS patients and showed the anticipated changes in RAS peptides. Taken together, evidence unequivocally supports the concept that ACE2 is critical in pulmonary function and its imbalance in COVID-19 infection contributes to the devastating lung consequences. An ACE2 activator, diminazene aceturate (DIZE) is a known antiprotozoal drug used in humans, but it has additional benefits including potent anti-inflammatory and antifibrotic activity. DIZE has been used in type 1 diabetes to prevent nephropathy and gastric inflammation. DIZE modulated the RAS by reducing serum Ang-II and the expression of AT1R, but it increased Ang-1-7 (7). DIZE not only increased ACE2 activity but also increased the expression of ACE2 in select cell types where DIZE inhibited the expression of IL-6, IL-8, and MCP-1 at both mRNA and protein levels following stimulation with lipopolysaccharide. Collectively, these results show that DIZE downregulates proinflammatory cytokine production by many distinct cell types and suggest that this drug may provide benefit to COVID-19 patients by reducing pulmonary inflammation and fibrosis, gut inflammation, and cytokine storm.
Conclusion As the global pandemic unfolds and rapidly spreads, there is an urgent need for basic and clinical studies to address the many unanswered questions posed by COVID-19. This Perspective has directed attention to the disruption of RAS in the lung, gastrointestinal tract, and bone marrow as possible mechanisms of SARS-CoV-2 disease pathogenesis. The dysregulated RAS can potentially impact clinical outcomes in individuals with diabetes resulting in increased morbidity and mortality. ACE2 has emerged as the pleiotropic regulator of the RAS, by metabolizing Ang-II into the beneficial peptide Ang-1-7, while being harmful as the SARS-CoV-2 receptor. Loss of ACE2 indirectly via proteolytic processing, autophagy, and shedding partly could not only drive lung pathology but also gut disease in individuals with diabetes infected with COVID-19. SARS-CoV-2, by downregulating intestinal ACE2-B0AT1, could promote leaky gut syndrome with elevated plasma bacterial lipopolysaccharides and/or peptidoglycans enhancing systemic inflammation. Careful targeting of the RAS axis may represent a strategy for improving clinical outcomes in subjects with diabetes infected with COVID-19.
Reference & Source information: https://diabetes.diabetesjournals.org/
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