key: cord-0736721-vdo6yoxl
authors: Hoevenaar, Martijn; Goossens, Dolf; Roorda, Janne
title: Angiotensin-converting enzyme 2, the complement system, the kallikrein-kinin system, type-2 diabetes, interleukin-6, and their interactions regarding the complex COVID-19 pathophysiological crossroads
date: 2020-12-06
journal: J Renin Angiotensin Aldosterone Syst
DOI: 10.1177/1470320320979097
sha: 4d68341664db3744ee87f504b75355187a66b9b3
doc_id: 736721
cord_uid: vdo6yoxl

Because of the current COVID-19-pandemic, the world is currently being held hostage in various lockdowns. ACE2 facilitates SARS-CoV-2 cell-entry, and is at the very center of several pathophysiological pathways regarding the RAAS, CS, KKS, T2DM, and IL-6. Their interactions with severe COVID-19 complications (e.g. ARDS and thrombosis), and potential therapeutic targets for pharmacological intervention, will be reviewed.

The aim of this review is to create a framework of different interconnected pathways that constitute the complex COVID-19 pathophysiological crossroads, as well as the interactions with common comorbidities (T2DM in particular).

First the SARS-CoV-2 virus and COVID-19 (including severe complications) will be introduced. Then, the COVID-19 relation with the RAAS will be reviewed, and a preliminary framework will be established. This framework will subsequently be expanded with the CS and the KKS. The interactions between COVID-19, T2DM, and IL-6, will be reviewed in light of this framework. Finally, some potential targets for therapeutic intervention will be discussed.

Abbreviations are listed at the end.

SARS-CoV-2 is a SSRNA + , enveloped virus from the beta-coronavirus family, with a structural surface spike (S) glycoprotein that primarily binds to the N-terminal domain of ACE2, predominantly, but not exclusively, on type-II pneumocytes. 1-3 SARS-CoV-2 decreases surface ACE2 expression through directly binding to ACE2, 4-6 followed by TMPRSS2-mediated proteolytic cleavage 3, 7, 8 and subsequent endocytosis. 1,3,5 TMPRSS2 is essential for SARS-CoV-2 membrane fusion and subsequent cellentry, 3, 7, 8 but other proteases (such as Furin) may facilitate SARS-CoV-2 cell-entry as well. 2, 5, 9 Surface ACE2 is further reduced via shedding, caused by Ang-II-mediated upregulation of ADAM-17 5,6,10 and androgen-mediated 8, 11 upregulation of TMPRSS2. 3, 7 Reduced ACE2 expression may also be modulated epigenetically via DNA-methylation processes, 12, 13 or via crosstalk with T2DM-induced hyperglycemia. 14, 15 The SARS-CoV-2-related disease is commonly referred to as COVID-19. 1, 7, 16 Common COVID-19 symptoms are fever, dry cough, sore throat, dyspnea, headache, and myalgia. 1, 12, 17 Some atypical symptoms are anosmia (loss of smell) [18] [19] [20] and diarrhea (which may present earlier than respiratory conditions). 1, 5, 17 Different sex and age groups have very biased severity and mortality of COVID-19, with male, old age, and comorbidity being the most affected. 1, 4, 15 T2DM, hypertension, and CVD are common COVID-19 comorbidities (which are likely related to a dysregulated RAAS) 5, 6, 21 and are associated with ARDS 15, 22, 23 and high fatality. 1, 23, 24 Currently, there is no approved and effective medication against COVID-19. 16, 22, 25 The protective mechanism during the early stages of a (viral) infection predominantly occurs through the innate immune system. 26-28 COVID-19 primarily suppresses the innate immune system, enabling the uncontrolled spread of the virus during the initial stages. [27] [28] [29] This explains a mild (sometimes even asymptomatic) presentation early on. 27, 28, 30 The high effectiveness of the innate immune system in children possibly explains why COVID-19 doesn't seem to affect them as much (if at all). 27,28,30 Differences in immunity 27,28,31 and gene expression 4, 12, 22 may contribute to COVID-19 severity. Severe COVID-19 complications are associated with excessive and dysregulated host immune responses, which may contribute to the development of lethal CRS and ARDS. [32] [33] [34] Acute respiratory distress syndrome ARDS, the most severe form of ALI, 35-37 is a clinical syndrome of noncardiogenic pulmonary edema. 38-40 ARDS is characterized by an excessive inflammatory response, 41-43 damage to both alveolar epithelial 38,40,41 and vascular endothelial 39,44,45 cells, the subsequent breakdown of the alveolar-capillary barrier integrity, 38,42,46 impaired AFC, 40,41,45 excessive interstitial and parenchymal neutrophil migration, 38,43,45 and activation of alveolar macrophages, platelets, and pro-coagulant processes. 42, 47, 48 This may result in diffuse alveolar damage, 42,49 pulmonary fibrosis, 37,50 and impaired gas exchange, 42,51 leading to (refractory) hypoxemia 35,38,42 and possibly organ dysfunction. 40, 47, 52 Uncontrolled inflammation leads to excessive and prolonged activation of neutrophils, 38, 43, 45 which are immune cells that play an important role in the regulation of IL-6 signaling 53-55 in the pathology of pulmonary inflammatory disorders. 38,43,56 Neutrophil-mediated ROS production (via NADPH oxidase), 57,58 plays an essential part in the immune response against pathogens via NET formation and direct cellular damage. 59-61 Excessive neutrophil recruitment therefore contributes significantly to the severity of inflammatory pneumonia. 56, 60, 62 In AFC, alveolar fluid is cleared via an ENaC-mediated osmotic gradient. 40, 41, 63 Disruption of ENaCs can lead to impaired AFC. 42, 62, 64 The ECM is important for the epithelial and endothelial barrier function, since it regulates intercellular interactions and controls the migration of fluid and molecules in the interstitial space. 42,65 Changes in ECM composition affect the mechanical properties of tight-junctions in alveolar epithelial and vascular endothelial cells, modulating the alveolar-capillary barrier function. 42, 66 Excess deposition of ECM proteins can lead to pulmonary fibrosis, 37,42,50 which may lead to chronic impairment of pulmonary function in ARDS survivors. 50 The amount of alveolar epithelial damage and impaired AFC capability are associated with impaired gas exchange and higher mortality. 41,42,62 Injury of the alveolar epithelium (not the vascular endothelium) determines the progression to pulmonary fibrosis. 42,67,68 Currently there is no specific treatment for post-ARDS pulmonary fibrosis other than supportive therapy. 50, 69 ARDS is one of the leading causes of death in ICU patients. 38,40,41 Current ARDS therapy mainly constitutes supportive treatments, such as mechanical ventilation. 51,70,71 This is predominantly effective in less severe cases, and may have serious side-effects. 38,70,71 High tidal volume mechanical ventilation upregulates ACE expression and Ang-II activity, 71 activates JNK and ERK 1/2 , 72 and increases pulmonary parenchymal IL-6 levels via excessive alveolar distention. 70 Mechanical ventilation may promote ventilator-induced ALI, which is characterized by inflammation, increased vascular permeability, interstitial pulmonary edema, parenchymal infiltration, fibrosis, and thrombosis. 42, 48, 71 The COVID-19-related ARDS may present atypically, in the sense that there is relatively well-preserved pulmonary compliance (despite the severity of hypoxemia), and systemic features of a hypercoagulable state. 73-75 To understand how and why, a trinity of interconnected systems will be discussed, starting with the RAAS.

To explain why changes in ACE2 and Ang-II levels are important in COVID-19, we need to discuss their interactions with other relevant systems, as well as their relation to comorbidities and complications.

If we exclusively focus on the RAAS, it is best described as a regulatory system with two axes that control vasoconstriction and vasodilation, 3, 76, 77 which play an essential role in maintaining hemodynamic homeostasis. 64,78,79 The classical ACE/Ang-II/AT1R axis promotes vasoconstriction. 37,80,81 Renin increases Ang-I, which is subsequently converted to Ang-II by ACE, 35,77,82 after which Ang-II exerts its cellular effects (predominantly via the AT1R). 58,79,83 The counterregulatory ACE2/Ang-(1-7)/ MasR axis promotes vasodilation. 3,76,77 ACE2 converts Ang-II to Ang-(1-7), which exerts its cellular effects predominantly via the MasR. 64, 79, 80 In a perfectly balanced RAAS, neither ACE nor ACE2 should be considered good or bad, as they are both required to maintain healthy homeostasis. Since ACE is required for either axis, Ang-II and ACE2 should be considered to be the main effectors of the RAAS. This balance can go either way, meaning low ACE2/high Ang-II or high ACE2/ low Ang-II. Since only low ACE2/high Ang-II is relevant regarding COVID-19, the focus will be on that type of RAAS imbalance in particular.

Ang-II will be considered first, after which ACE2 will be discussed.

Ang-II is considered to be the major player in the ACE/ Ang-II/AT1R axis. 41,83,84 A dysregulated RAAS (and associated elevated Ang-II levels) has many detrimental effects. Ang-II upregulates Aldosterone production and promotes hypertension, 83 (Figure 1 ). ERK 1/2 , JNK and p38-MAPK are members of the MAPK family, and are preferentially activated by inflammation and environmental stresses (JNK and p38-MAPK in particular). 97-99 MAPK signaling plays a crucial role in regulating cell apoptosis, inflammatory responses, and cell-cell junction formation. 14,72,96 NF-κB is a transcription factor family that plays an important immunoregulatory role, 44,100,101 and modulates the production of inflammatory cytokines 44,86,89 and NADPH oxidase subunits. [102] [103] [104] Ang-II-induced ROS production effectively induces insulin resistance, 79,86,94 and exacerbates T2DM. 64, 86, 89 Insulin resistance impairs the PI3K/Akt/eNOS pathway, 94, 105, 106 subsequently reducing glucose uptake and NO production. 86,88,89 Insulin signaling, and the role of Ang-II in insulin resistance, will be further discussed in the T2DM section. To understand the importance of Ang-II-mediated reduction of NO bioavailability in COVID-19, we will first consider the vascular endothelium.

The inner surface of the vascular tree is lined with a continuous monolayer of endothelial cells (joined together by tight-junctions), forming a protective selective permeability barrier between the circulating blood and the extravascular tissue. 39,107,108 The endothelium is a metabolically active homeostatic organ, regulating the tone, structure and permeability of the vascular system in response to different stimuli (e.g. shear stress, ACh, and insulin). 46, 78, 104 Limited vascular permeability is a function of a balanced endothelial phenotype, which constitutes smooth muscle relaxation, as well as low platelet activation and low fibrin formation. 78, 109, 110 Endothelial dysfunction disrupts this balance and predisposes the vascular wall to inflammation, platelet activation, dysregulated coagulation, thrombosis, and increased vascular permeability. 39, 48, 111 Both the disruption of endothelial tight-junctions 39,72,108 and impaired NO bioavailability 104, 109, 112 are two important causes of endothelial dysfunction and increased vascular permeability. ROS-mediated MAPK signaling is responsible for disruption of endothelial tight-junctions. 39,72,108 Impaired NO bioavailability occurs via eNOS uncoupling, 104, 109, 113 reduced eNOS activity, 74, 112, 114 or ROSscavenging. 55, 104, 115 Prolonged and excessive vascular permeability can result in tissue damage, organ dysfunction, or even death. 116, 117 Impaired NO bioavailability plays a role in thrombosis, due to the hampering effect of NO on ROS-mediated upregulation of platelet activation, suggesting that either decreased NO bioavailability or increased ROS production is able to induce thrombosis. 114 initiates the coagulation pathway by activating platelets and pro-coagulant cascades, while reducing anti-coagulant components and fibrinolysis. 42, 114 This results in pulmonary capillary microthrombi and fibrin deposition in parenchymal and interstitial compartments, 42 which is characterized by observed high D-dimer and von Willebrand Factor in some COVID-19 patients. 21, 119, 120 During an inflammatory state, endothelial cells release von Willebrand Factor, 110,120 which represents an important thrombotic risk factor. 48,121 Von Willebrand Factor is a large adhesive glycoprotein, synthesized by endothelial cells, 46,110,120 and is critical for platelet adhesion and aggregation. 48,121 ABO blood group genes affect von Willebrand Factor expression, as well as their susceptibility to proteolytic degradation via ADAMTS13. 122 This is a possible explanation why ABO blood group type may be differentially related to COVID-19 severity. 122 Ang-II-mediated ROS production 58,90,91 and decreased NO bioavailability 79,94,123 promote vascular permeability 41,81,83 and thrombosis 6,80,82 ( Figure 1 ). Ang-II-mediated disruption of ENaCs impairs AFC, 41,64,124 exacerbating pulmonary edema. 40,62,63 These are essential components of ARDS, 41,42,62 which is a severe COVID-19 complication. 25,76,125 Ang-II is significantly elevated in COVID-19 patients and is highly associated with viral load and lung injury. 21, 76, 125 Angiotensin-converting enzyme 2

The ACE2/Ang-(1-7)/MasR axis can mitigate Ang-IImediated negative effects. 77, 79, 81 ACE2 is a homologue of ACE, 78,82,84 and a key component of the RAAS. 77,81,126 ACE2 is a two-part type-I transmembrane protein, consisting of a glycosylated extracellular N-terminal domain (containing the SARS-CoV-2-binding carboxypeptidase site), and an intracellular C-terminal cytoplasmic tail. 3, 127, 128 The extracellular catalytic domain of ACE2 can be cleaved and released by ADAM-17 5,6,76 or TMPRSS2. 2, 3, 8 ACE2 is widely expressed in the heart, kidneys, lungs, CNS, and intestines, 80,82,84 and is present in type-II pneumocytes and endothelial cells. 6 Low ACE2 expression has been associated with hypertension, CVD, T2DM, inflammation, and ARDS, 4-6 which happen to be risk factors for (severe) COVID-19 complications. 1, 15, 23 Since ACE2 is the SARS-CoV-2 cell-entry point, 2,3,6 there has been speculation that elevated ACE2 expression may increase susceptibility for SARS-CoV-2 infection. 140-142 ACE2 expression is higher in females than in males, 4,134 and declines with age 5, 141 (in men more so than in women). 6, 143 This can be explained by the upregulation of ACE2 expression by Estrogen, 4, 131 and the X-chromosomal location of the ACE2 gene 3,129,144 (which is regulated epigenetically via DNA methylation). 12,13 DNA methylation is associated with biological age, 12, 145, 146 which suggests that biological age may be a more accurate risk factor for severe COVID-19 complications compared to chronological age. 13, 147 This pattern of ACE2 expression may partly explain why elevated ACE2 levels possibly have no negative effects on COVID-19 susceptibility. 4, 6, 134 Also, there is a negative correlation between ACE2 expression and COVID-19 fatality. 4,5,144 SARS-CoV-2-induced downregulation of ACE2 expression may especially be detrimental in people with comorbidities, since they initially have a lower ACE2 baseline. 4,6,21 Additional COVID-19-mediated ACE2 deficiency may amplify the RAAS dysregulation, 5,6,76 resulting in upregulation of Ang-II, which is indeed significantly elevated in COVID-19 patients. 21, 76, 125 In the lungs, such dysregulation can induce the progression of inflammatory and thrombotic processes, because Ang-II is now unopposed by ACE2. 6, 21, 125 This suggests that ACE2 may not be the culprit in COVID-19, but may actually have an important protective role, despite the ACE2-mediated cellentry mechanism of SARS-CoV-2. 5,76,134 A low ACE2 expression (or reserve) may contribute to the progression of COVID-19 to a (more) severe or fatal stage. 4, 6, 125 Because of the high intrinsic affinity of ACE2 with the SARS-CoV-2 spike (S1) proteins, 6 a lower ACE2 expression may not affect the susceptibility for SARS-CoV-2 infection at all. 6, 127 Although many effects of ACE2 have been attributed to the downregulation of Ang-II levels, other substrates play a major role in ACE2-related functions as well. 56, 64, 81 The framework we have now established consists of the following hypothesis: "a SARS-CoV-2-induced RAAS imbalance, comprised of reduced ACE2 expression (and a subsequent elevated Ang-II activity), plays a role in severe COVID-19 complications."

There are still many loose ends in this narrative. In order to connect these, two more systems will be discussed, that is, the CS and the KKS. The CS and the KKS are linked. 107, 148, 149 The KKS and the RAAS are linked as well. 25,56,64 The RAAS, CS, and KKS, form a trinity of systems with several regulatory axes contributing to severe COVID-19 complications.

The CS is an important component of the innate immune system, involved in host defense against micro-organisms, clearance of immune complexes and removal of apoptotic cells, [149] [150] [151] and is intrinsically linked to the coagulation pathway. 21, 151, 152 The CS is a key mediator of lung damage during (corona virus) infections, raising the possibility that CS activation may play a role in severe COVID-19 complications. 16, 74, 153 Although most CS components are synthesized in the liver, type-II pneumocytes provide local CS proteins. [154] [155] [156] The CS components C1, C3 a , C5 a , as well as the C5 b -C9 MAC, all contribute to increased endothelial permeability. 107, 157, 158 The CS can be activated via three pathways, that is, the classical, lectin, or alternative pathway. 154, 159, 160 The classical pathway entails the creation of immune complexes with IgM/IgG antibodies, binding predominantly to pathogenic antigens. 107, 159, 161 C1 binds to the antibody and forms C3 and C5, via initiating a series of enzymatic cascades. 107, 154, 162 C3 and C5 are both cleaved to C3 a /C3 b and C5 a /C5 b respectively. 107,154,160 C3 a and C5 a act as chemotactic agents for phagocytes. 107,151,154 C3 b is involved in opsonization of pathogens that are subsequently destroyed by phagocytes. 107,154,159 C5 b -C9 forms a MAC that induces cell-lysis by punching holes through their membranes. 107, 154, 161 The lectin pathway involves the interaction of MBL with the pathogen (or the surface of a pathogen-infected cell), followed by the subsequent binding and activation of MASP2, directly activating similar CS cascades as in the classical pathway. 74, 153, 154 The alternative pathway involves a spontaneous conformation change of C3, and after a short cascade, C3 is cleaved into C3 a and C3 b without the use of antibodies, leading to similar cascades as the classical pathway. 151, 154, 163 The CS is inhibited by the SerPin C1 INH via inhibition of C1 in the classical pathway, MASP2 in the lectin pathway, and C3 b in the alternative pathway. 107, 149, 164 Excessive CS activation can lead to inflammation and (excessive) neutrophil recruitment via opsonization and (via C3 a -and C5 a -mediated) 107,153,156 chemotaxis. 16, 148, 153 Excessive CS activation (on the endothelial surface) can lead to vascular problems, for example, endothelial damage (via MAC-induced lysis), 74,148,154 vascular permeability, 107, 148, 158 thrombosis, 148, 151, 152 (diffuse) TMA, 159, 162, 165 and DIC. 161, 166, 167 This is how excessive CS activation exacerbates ARDS, 16 ,74,154 pulmonary fibrosis, 50,168,169 and possibly organ dysfunction. 16, 151, 159 In at least a subset of severe COVID-19 patients an excessive CS activation is found via the lectin pathway, 153, 170, 171 as demonstrated by elevated C5 b -C9 MAC components, MBL-MASP2 in the pulmonary microvasculature, and parenchymal neutrophils. 74 This is consistent with sustained and systemic CS activation and an associated pro-coagulant state. 21 ,74 A possible modus operandi for additional CS activation via the lectin pathway in COVID-19 is the binding of SARS-CoV-2 N-proteins to MASP2. 153 This leads to excessive CS activity, 153, 171 further exacerbating CS-mediated MAC formation, inflammation, and concurrent activation of the coagulation pathway, 21,74 resulting in ARDS 16, 153 and thrombosis 74,170 ( Figure 2 ). The observed high D-dimer and von Willebrand Factor (and its associated thrombotic activity) in severe COVID-19 patients, 111, 119, 120 can at least be partially explained by excessive CS activation (and associated MAC-mediated endothelial dysfunction), followed by an activated coagulation pathway. 74, 153, 159 Our framework can now be expanded with the hypothesis: "an excessive CS activation plays a significant role in severe COVID-19 complications."

The CS is not only linked to the coagulation pathway, 151, 161, 166 but to the KKS as well, 107, 148, 149 which will be discussed next.

The KKS, like the CS, is an important part of the innate immune system, 149, 172, 173 and is activated during inflammation. 148, 164, 174 The KKS consists of Hageman Factor (Factor XII), PK, HK, the proteolytic KK enzymes, and stimulation; inhibition effector peptides, such as BK (and its active metabolite des-Arg 9 -BK). 107, 149, 164 Factor XII gets activated via inflammatory processes and converts to Factor XII a , which in turn converts PK into KK, initiating the kinin cascade 107 The KKS and the CS are intrinsically linked at multiple levels, and are both activated during (vascular) inflammation (i.e. via gC1 q R, which binds both C1 q and HK). 107, 148, 149 Simultaneous and uncontrolled excessive activation of both the KKS and CS (on the endothelial surface) is largely responsible for increased vascular permeability and edema. 107, 148, 149 KK, which cleaves HK and subsequently releases BK, also cleaves and activates C3. 148, 190, 191 The KKS 107, 148, 149 and CS [150] [151] [152] are both intrinsically linked to the coagulation pathway. The endothelial permeabilityinducing effect of the C5 b -C9 MAC is regulated by BK. 107, 192, 193 The KKS and CS are both inhibited by C1 INH . 148, 149, 164 ACE2 degrades the otherwise stable des-Arg 9 -BK. 56,64,81 SARS-CoV-2 reduces ACE2 expression. 3,6,125 A reduction in pulmonary ACE2 subsequently increases Ang-II 5, 125, 194 and impairs the degradation of the des-Arg 9 -BK/B1R axis of the KKS. 6, 25, 56 This exacerbates neutrophil migration 56,148,174 and ARDS. 25,56,75 The des-Arg 9 -BK/B1R axis of the KKS is not affected by corticosteroids, [195] [196] [197] which means that as long as the virus is present, ACE2 will not be, and the kinin-induced ARDS will persist. 75 We now have established multiple connections between the RAAS, CS, KKS, and the coagulation pathway. In our trinity of systems, the RAAS 3,76,77 controls vasoconstriction and vasodilation, whereas the KKS 85,180,181 and the CS 107, 158, 198 control vascular permeability and vasodilation. ACE2 is the one ring that rules them all 75 (Figure 3 ). The SerPin C1 INH effectively suppresses the KKS, 107, 149, 164 the coagulation pathway, 107, 151, 152 and all three pathways of the CS. 150, 152, 176 Our framework can now be further expanded with the hypothesis: "a SARS-CoV-2-induced reduction of ACE2 expression directly causes a disruption and excessive activation of the KKS, which is not only able to further activate an already active CS, but directly plays a significant role in the exacerbation of severe COVID-19 complications."

Next, the T2DM interactions with our trinity of systems will be discussed. 

T2DM is considered to be a metabolic disease, comprising insulin resistance and pancreatic β-cell dysfunction, resulting in insulin deficiency and subsequent hyperglycemia. 99, 104, 199 T2DM is characterized by comorbid conditions of CVD 89, 104, 200 and hypertension. 89, 201, 202 T2DM is also associated with vascular problems, for example, endothelial dysfunction, vascular permeability, platelet dysfunction, and hypercoagulation. 113, 203, 204 98, 199, 221 Finally, the RAAS may be disrupted in expanding visceral adipose tissue, exacerbating inflammation and insulin resistance. 6, 222, 223 Insulin resistance P(Tyr)IRS-1 is required for insulin-stimulated activation of the PI3K/Akt/eNOS pathway 99, 206, 224 and multiple downstream effectors that promote glucose uptake and NO production. 112, 225, 226 NO has vasoprotective effects, 79,227,228 and its bioavailability depends on the balance between the rate of its eNOS-mediated production and its ROSmediated inactivation. 104, 109, 229 Increased P(Ser)IRS-1 and decreased P(Tyr)IRS-1 98,224,230 (both induced by JNK and ERK 1/2 ) disrupt insulin signaling, 94, 199, 206 preventing activation of the PI3K/Akt/ eNOS pathway. 99, 115, 231 Chronic P(Ser)IRS-1 also targets IRS-1 for degradation or migration to inaccessible subcellular compartments. 54, 89, 232 Hyperinsulinemia, caused by insulin resistance, activates both JNK 230,232,233 and ERK 1/2 . 88,234,235 Subsequently this further stimulates P(Ser)IRS-1, 97,99,230 which is how hyperinsulinemia exacerbates insulin resistance. 94, 232, 236 Hyperinsulinemia also upregulates Ang-II, which is how insulin resistance may disrupt the RAAS. 89, 237, 238 Ang-II-mediated ROS production increases P(Ser) IRS-1 79,88,94 and decreases P(Tyr)IRS-1, 86,89,105 effectively inducing insulin resistance 87,239,240 (Figure 1) . A vicious cycle between the RAAS and insulin resistance has now been created. 89, 241, 242 Insulin resistance is a risk factor for T2DM, 86 

The progression from insulin resistance to T2DM implicates the inability of pancreatic β-cells to compensate for increased insulin demand. 53, 221, 244 Sustained JNK activation causes pancreatic β-cell dysfunction, 230,232 especially in obese individuals with an exacerbated inflammatory milieu. 99, 199, 221 IL-6 increases the proliferation of α-cells and apoptosis of β-cells in the pancreas, 53,245,246 suggesting a link between IL-6 and T2DM. 208, 218, 247 The role of IL-6 in the proliferation of α-cells may initially compensate for the impaired β-cells in T2DM and contributes to limit hyperglycemia. 53, 245, 248 Hyperglycemia increases IL-6 levels, both systemically and locally in pancreatic Langerhans islets, 53,249,250 and promotes β-cell death 99, 246, 251 (Figure 1 ).

In T2DM, the KKS is activated and kinins cause damage to pancreatic Langerhans islets, suggesting a link between the KKS and T2DM. 85 Furthermore, in T2DM, ACE2 expression is downregulated, 15, 133 and increased Ang-II plays a part in reducing β-cell function via ROS-mediated apoptosis, 89,252 suggesting a link between RAAS disruption and T2DM. 64,86,89

Pancreatic β-cell dysfunction leading to T2DM results in insulin deficiency and subsequent hyperglycemia, 104, 115, 221 which has a plethora of detrimental effects.

Hyperglycemia increases the production of IL-6 53,55,250 and AGEs. 104 104, 109, 275 ). Hyperglycemia-mediated ROS production effectively promotes endothelial dysfunction. 104, 108, 113 Therefore hyperglycemia increases vascular permeability, 39,115,276 and subsequently promotes (pulmonary) edema. 55, 203, 277 Hyperglycemia also promotes thrombosis, 24,113,118 via platelet activation, increased coagulation factors, and decreased fibrinolysis. 114, 205, 278 Furthermore, hyperglycemia (even short-term) dysregulates both the innate and adaptive immune system. 24, 55, 265 This may affect neutrophil-IL-6 signaling, chemotaxis, phagocytosis, respiratory burst, anti-microbial activity, and production of inflammatory cytokines. 23,55,266 This creates a milieu in which SARS-CoV-2 can flourish. 15, 23, 24 Finally, hyperglycemia also interferes with the CS, upregulating expression of several CS component genes, hindering C3 b -mediated opsonization and IG-function via glycation. 55, 279, 280 Well-controlled blood-glucose levels reduce the risk of severe COVID-19 complications. 23,24,281 Therefore, our framework can now be further expanded with the hypothesis: "T2DM-induced hyperglycemia is not only just a risk factor for severe COVID-19 complications, but is actually exacerbated (possibly even induced) by Next, the role of IL-6 signaling, and the interactions with T2DM and COVID-19 complications, will be discussed.

IL-6 has both pro-and anti-inflammatory characteristics. 53,208,282 Dysregulated or excessive IL-6 signaling is considered to be involved in insulin resistance, 104, 206, 247 βcell dysfunction, 53,245,251 T2DM, 53,208,218 and CVD. 208, 283, 284 Various cell types can locally produce IL-6, 284-286 which can be transported through the circulation, affecting more distant regions in the body. 53 Immune cells are simultaneously both sources and targets of IL-6. 53,283,286 Betacoronavirus infection of immune cells, for example, monocytes, macrophages, and dendritic cells, will result in their activation and subsequent secretion of IL-6. 287 To exert its physiological effects, IL-6 utilizes both the classic and trans signaling pathway. 208, 213, 288 In classic signaling, IL-6 binds to mIL-6R and forms a complex with gp130, after which downstream signaling is mediated via JAK and STAT3. 283, 284, 286 In trans signaling, extracellular sIL-6R can bind to IL-6, forming a complex with gp130, after which downstream signaling is mediated via JAK and STAT3 in cells that do not express mIL-6R 53,284,289 (such as endothelial 53,116,284 and pancreatic α and β cells 245, 246, 248 ). IL-6 classic signaling is mostly involved in anti-inflammatory activities, whereas IL-6 trans signaling is mostly involved in pro-inflammatory activities. 53, 213, 289 Most cells express gp130, while mIL-6R is mostly found on monocytes, macrophages, neutrophils, and αand β-cells of pancreatic Langerhans islets. 53, 208, 245 The widespread expression of gp130 on most cell types, including endothelial cells, dramatically expands the range of IL-6 target cells using trans signaling. 208, 284, 287 In order to prevent a systemic response to IL-6 trans signaling, sgp130 specifically blocks trans signaling without affecting classical signaling, and basically constitutes a physiological buffer for circulating IL-6. 53, 284, 288 IL-6 activates ERK 1/2 , 54,206,290 JNK, [291] [292] [293] and p38-MAPK, 89, 294, 295 subsequently initiating crosstalk with NF-κB 44,104,249 (Figure 1 ). This IL-6-mediated MAPK signaling decreases P(Tyr)IRS-1 54,104,247 and increases P(Ser)IRS-1, 206, 296, 297 inducing insulin resistance 53,89,296 and impairing NO production. 54,206,290 IL-6-mediated MAPK signaling also disrupts endothelial tight-junctions 116, 285, 298 and induces endothelial cell contraction. 285, 299 Therefore, IL-6 effectively increases vascular permeability 70,104,285 and exacerbates edema 116 and lung injury/ ARDS. 70,300,301 The lack of mIL-6R on endothelial cells indicates trans signaling as the main mechanism involved in the detrimental effects of IL-6 on vasculature. 53, 116, 284 IL-6 also induces epigenetic changes (regarding genes involved in insulin signaling) via DNMT-induced alteration of DNA methylation patterns, promoting endothelial dysfunction 54,302 and insulin resistance. 213, 303, 304 IL-6 levels are significantly elevated in COVID-19 patients. 22, 305, 306 IL-6 plays an important role in CRS, 16, 306, 307 exacerbates ARDS, 70,287,305 and predicts mortality 282, 305, 308 (Figure 4) .

Our framework can now be further expanded with the hypothesis: "Excessive IL-6 trans signaling significantly contributes to severe In the last section, we will briefly discuss some potential attractive therapeutic targets and their pharmacological interactions. 

Due to the lack of approved targeted medication for COVID-19, 16, 22, 309 and developing an effective and safe vaccine may require some time, it is recommended to explore multiple potential therapeutic targets to mitigate severe COVID-19 complications.

Since TMPRSS2 is essential for SARS-CoV-2 membrane fusion and subsequent cell-entry, 2,3,7 inhibition of TMPRSS2 activity can potentially prevent severe COVID-19 complications. 3, 8, 310 Nafamostat Mesylate, a clinically approved and safe medication for pancreatitis, inhibits TMPRSS2-mediated SARS-CoV-2 envelope-membrane fusion and subsequent cell-entry. 3 Because ACE-inhibitors and ARBs upregulate ACE2 expression, 1,76,80 and SARS-CoV-2 uses ACE2 for cellentry, 3, 6, 8 it has been speculated that ACE-inhibitors and ARBs can have negative effects in COVID-19 patients. [140] [141] [142] Multiple studies however, show no association between both ACE-inhibitors and ARBs, and increased susceptibility for COVID-19 or the severity of its complications. [320] [321] [322] Various experimental models 37,71,76 show that rhsACE2 activates the protective ACE2/Ang-(1-7)/MasR-axis of the RAAS, 71,76,80 degrades des-Arg 9 -BK, 75 and improves ARDS symptoms. 44,71,82 Therapeutic use of rhsACE2 in COVID-19 patients may have beneficial effects, such as effectively sequestering circulating viral particles to prevent S-protein interactions with membrane-bound ACE2, while simultaneously rebalancing the RAAS into a more protective equilibrium. 6, 76, 323 Clinical-grade rhsACE2 can significantly inhibit SARS-CoV-2 infections in vitro (in a dose-dependent manner), reduce viral load by a factor of 1.000 -5.000, 324 and is currently being tested in a phase-II trial in Europe. 5, 127 

Inhibiting an excessively active CS may reduce severe COVID-19 complications, for example, ARDS, 153 Eculizumab is a monoclonal antibody that binds to C5 and prevents cleavage into C5 a and C5 b , as well as the formation of the C5 b -C9 MAC, 16, 74, 325 and may also reduce the risk of TMA 162, 163, 165 and DIC. 166, 326 Inhibiting the KKS, either by inhibiting kinin production or blocking B1R/B2R, may improve COVID-19induced ARDS. 25,75,327 Since B1R is upregulated during inflammation, 56,107,180 and des-Arg 9 -BK is much more stable than BK, 148,164 the des-Arg 9 -BK/B1R axis is of major importance in vascular permeability during inflammation. 164 Unfortunately, there currently is no approved B1Rinhibitor available. 25,75,327 Icatibant is a selective B2R antagonist, traditionally used for hereditary angioedema, 25,107,164 and may improve severe COVID-19 complications. 75,327 B2R inhibition, besides reducing the KKS, also reduces the CS. 148 C1 INH inhibits the activation of both the CS and KKS, 148 qualifying it as an attractive potential therapeutic option for severe COVID-19 complications. Plasma-derived C1 INH , a first-line therapy for hereditary angioedema, appears to be safe. 328 Ruconest, a recombinant human C1-esteraseinhibitor, has achieved some good preliminary results in treating COVID-19 patients, according to a press release. 329

IL-6 inhibition mitigates vascular permeability and alveolar-capillary barrier disruption. 70, 116, 309 Tocilizumab is a monoclonal antibody, mainly used for the treatment of rheumatoid arthritis. 22, 308, 330 It inhibits IL-6 305,306,331 via binding to both mIL-6R and sIL-6R, resulting in complete blockade of both classic and trans IL-6 signaling pathways. 287, 308, 330 Disruption of both proand anti-inflammatory activities of IL-6 may cause sideeffects, for example, secondary (bacterial or fungal) infections, liver malfunction, or hypercholesterolemia. 53,208 Despite the possible side-effects, preliminary studies show that Tocilizumab appears to be effective and safe regarding severe COVID-19 complications. 22, 306, 309 Tocilizumab however, seems less effective in hyperglycemic patients. 332 Sgp130Fc (a recombinant version of sgp130) specifically blocks IL-6 trans signaling, without affecting the anti-inflammatory and protective classical IL-6 signaling. 53,208,288 Therefore sgp130Fc may result in better therapeutic outcomes with fewer undesired side-effects. 53, 208, 333 Sgp130Fc has demonstrated robust efficacy in the treatment of several autoimmune and inflammatory conditions 53,288 with fewer side-effects than global IL-6-inhibitors. 53,208,333 Sgp130Fc may potentially have therapeutic benefits for COVID-19-induced ARDS. 333

We have established the concluding framework regarding the COVID-19 pathophysiological crossroads: "COVID-19 disrupts the RAAS balance via reduction of . Ang-II, excessive KKS and CS activation, hyperglycemia, and IL-6 trans signaling, all contribute significantly to severe COVID-19 complications (e.g. ARDS and thrombosis/DIC)." The RAAS, CS, KKS, and the coagulation pathway, are all intrinsically connected sensitive systems, with ACE2 as master regulator. Elevated ACE2 baseline levels may protect from severe COVID-19 complications.

There are no effective approved medications against COVID-19 yet, and a vaccine may be a long way off. However, several attractive therapeutic targets in the RAAS, CS, and KKS have shown promising preliminary results against severe COVID-19 complications.

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The author(s) received no financial support for the research, authorship, and/or publication of this article. 

A comprehensive literature review on the clinical presentation, and management of the pandemic coronavirus disease 2019 (COVID-19)

SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells

ACE2: the key molecule for understanding the pathophysiology of severe and critical conditions of COVID-19: demon or angel?

Individual variation of the SARS-CoV2 receptor ACE2 gene expression and regulation

Angiotensin converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system

The pivotal link between ACE2 deficiency and SARS-CoV-2 infection

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

TMPRSS2 and COVID-19: serendipity or opportunity for intervention?

ACE2 shedding and furin abundance in target organs may influence the efficiency of SARS-CoV-2 entry

Angiotensin II induced proteolytic cleavage of myocardial ACE2 is mediated by TACE/ADAM-17: a positive feedback mechanism in the RAS

Prostate-localized and androgen-regulated expression of the membranebound serine protease TMPRSS2

DNA methylation analysis of the COVID-19 host cell receptor, angiotensin I converting enzyme 2 gene (ACE2) in the respiratory system reveal age and gender differences

Methylation pathways and SARS-CoV-2 lung infiltration and cell membrane-virus fusion are both subject to epigenetics

Calcitriol regulates angiotensin-converting enzyme and angiotensin convertingenzyme 2 in diabetic kidney disease

COVID-19, diabetes mellitus and ACE2: the conundrum

Eculizumab treatment in patients with COVID-19: preliminary results from real life ASL Napoli 2 Nord experience

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Non-neural expression of SARS-CoV-2 entry genes in the olfactory epithelium suggests mechanisms underlying anosmia in COVID-19 patients

Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study

Anosmia and ageusia: common findings in COVID-19 patients

Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: a novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis

Effective treatment of severe COVID-19 patients with tocilizumab

and diabetes prevention

Angiotensin II and the development of insulin resistance: implications for diabetes

Mitogenactivated protein kinase-activated protein kinase 2 in angiotensin II-induced inflammation and hypertension: regulation of oxidative stress

Oxidative stressmediated effects of angiotensin II in the cardiovascular system

Angiotensin II-induced production of mitochondrial reactive oxygen species: potential mechanisms and relevance for cardiovascular disease

ERK1/2 activation by angiotensin II inhibits insulin-induced glucose uptake in vascular smooth muscle cells

Angiotensin II impairs the insulin signaling pathway promoting production of nitric oxide by inducing phosphorylation of insulin receptor substrate-1 on Ser312 and Ser616 in human umbilical vein endothelial cells

Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice

Activation of MAPKs by angiotensin II in vascular smooth muscle cells metalloprotease-dependent EGF receptor activation is required for activation of ERK and p38 MAPK but not for JNK

Modulation of insulin receptor substrate-1 tyrosine phosphorylation and function by mitogen-activated protein kinase

Emerging role of the Jun N-terminal kinase interactome in human health

Role of c-Jun N-terminal kinase (JNK) in obesity and type 2 diabetes

Temperature regulates NF-κB dynamics and function through timing of A20 transcription

NF-kappaB: two sides of the same coin

NF-κB regulates phagocytic NADPH oxidase by inducing the expression of gp91phox

Regulation of NADPH oxidase subunit p22(phox) by NF-kB in human aortic smooth muscle cells

Insights into the molecular mechanisms of diabetes-induced endothelial dysfunction: focus on oxidative stress and endothelial progenitor cells

Angiotensin II inhibits insulin signaling in aortic smooth muscle cells at multiple levels. A potential role for serine phosphorylation in insulin/angiotensin II crosstalk

Crosstalk between insulin and angiotensin II signalling systems

Cross-talk between the complement and the kinin system in vascular permeability

Vascular endothelial tight junctions and barrier function are disrupted by 15(S)-hydroxyeicosatetraenoic acid partly via protein kinase C-mediated zona occludens-1 phosphorylation at threonine 770/772

Oxidative stress in endothelial cell dysfunction and thrombosis

Endothelial cell control of thrombosis

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation

Biochemical pathways for microvascular complications of diabetes mellitus

Thrombosis and vascular inflammation in diabetes: mechanisms and potential therapeutic targets

Diabetes and the pulmonary circulation

Interleukin-6 promotes a sustained loss of endothelial barrier function via Janus kinase-mediated STAT3 phosphorylation and de novo protein synthesis

Sepsis and endothelial permeability

Oxidative stress in atherogenesis and arterial thrombosis: the disconnect between cellular studies and clinical outcomes

Severe COVID-19 infection associated with endothelial activation

Targeting raised von Willebrand factor levels and macrophage activation in severe COVID-19: consider low volume plasma exchange and low dose steroid

Relationship between ABO blood group and von Willebrand factor levels: from biology to clinical implications

Relationship between the ABO blood group and the COVID-19 susceptibility

Angiotensin II limits NO production by upregulating arginase through a p38 MAPK-ATF-2 pathway

Regulation of alveolar fluid clearance and ENaC expression in lung by exogenous angiotensin II

Downregulation of ACE2 induces overstimulation of the renin-angiotensin system in COVID-19: should we block the renin-angiotensin system?

ACE and ACE2: their role to balance the expression of angiotensin II and angiotensin-(1-7)

Blockade of SARS-CoV-2 infection by recombinant soluble ACE2

Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia

The emerging role of ACE2 in physiology and disease

Potent neutralization of 2019 novel coronavirus by recombinant ACE2-Ig

Angiotensin converting enzyme 2 contributes to sex differences in the development of obesity hypertension in C57BL/6 mice

The ACE2/Ang-(1-7)/ Mas axis can inhibit hepatic insulin resistance

Angiotensin converting enzyme 2: a new important player in the regulation of glycemia

Organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of COVID-19

ACE2 and the homolog collectrin in the modulation of nitric oxide and oxidative stress in blood pressure homeostasis and vascular injury

ACE2 activation promotes antithrombotic activity

Angiotensin-converting enzyme 2-angiotensin (1-7)-Mas axis prevents pancreatic acinar cell inflammatory response via inhibition of the p38 mitogen-activated protein kinase/nuclear factor-κB pathway

Angiotensin-(1-7)-ACE2 attenuates reactive oxygen species formation to angiotensin II within the cell nucleus

ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function

The dilemma of coronavirus disease 2019, aging, and cardiovascular disease: insights from cardiovascular aging science

The differential expression of the ACE2 receptor across ages and gender explains the differential lethality of SARS-Cov-2 and suggests possible therapy

Inhibitors of the renin-angiotensin-aldosterone system and Covid-19

Age-and gender-related difference of ACE2 expression in rat lung

COVID-19 and individual genetic susceptibility/receptivity: role of ACE1/ACE2 genes, immunity, inflammation and coagulation. Might the double X-chromosome in females be protective against SARS-CoV-2 compared to the single X-chromosome in males?

Using DNA methylation profiling to evaluate biological age and longevity interventions

DNA methylation biomarkers in aging and age-related diseases

Biomarkers of biological age as predictors of COVID-19 disease severity

Blockade of the kallikrein-kinin system reduces endothelial complement activation in vascular inflammation

The plasma bradykininforming pathways and its interrelationships with complement

Interaction between the coagulation and complement system

Interactions between coagulation and complement-their role in inflammation

Molecular intercommunication between the complement and coagulation systems

Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation

Complement system in lung disease

Biosynthesis of the third and fifth complement components by isolated human lung cells

Pulmonary alveolar type II epithelial cells synthesize and secrete proteins of the classical and alternative complement pathways

Synergistic enhancement of chemokine generation and lung injury by C5a or the membrane attack complex of complement

Vascular permeability changes induced by complement-derived peptides

Will complement inhibition be the new target in treating COVID-19 related systemic thrombosis?

Complement-tapping into new sites and effector systems

Complementcoagulation cross-talk: a potential mediator of the physiological activation of complement by low pH

Extra-renal manifestations of complement-mediated thrombotic microangiopathies

Complement C5-inhibiting therapy for the thrombotic microangiopathies: accumulating evidence, but not a panacea

Icatibant, the bradykinin B2 receptor antagonist with target to the interconnected kinin systems

Complementmediated thrombotic microangiopathy associated with lupus nephritis

Complement, thrombotic microangiopathy and disseminated intravascular coagulation

Complement changes and disseminated intravascular coagulation in Plasmodium falciparum malaria

Crosstalk between TGF-β1 and complement activation augments epithelial injury in pulmonary fibrosis

Complement activation products in idiopathic pulmonary fibrosis: relevance of fragment Ba to disease severity

Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS): an atypical acute respiratory distress syndrome working hypothesis

Severe COVID-19 infection and thrombotic microangiopathy: success doesn't come easily

Interaction of the human contact system with pathogens-an update

The plasma contact system as a modulator of innate immunity

Activation of kinin B1 receptors induces chemotaxis of human neutrophils

An update on factor XI structure and function

Complement, kinins, and hereditary angioedema: mechanisms of plasma instability when C1 inhibitor is absent

Human urinary kallikrein converts inactive to active renin and is a possible physiological activator of renin

Isolation of completely inactive plasma prorenin and its activation by kallikreins: a possible new link between renin and kallikrein

Bradykinin and des-Arg(9)-bradykinin metabolic pathways and kinetics of activation of human plasma

Role of the B(2) receptor of bradykinin in insulin sensitivity

Bradykinin-regulated interactions of the mitogen-activated protein kinase pathway with the endothelial nitric-oxide synthase

Induction of B(1)-kinin receptors in vascular smooth muscle cells: cellular mechanisms of MAP kinase activation

Tissue kallikrein mediates pro-inflammatory pathways and activation of protease-activated receptor-4 in proximal tubular epithelial cells

Cellular localisation of the kinin B1R in the pancreas of streptozotocintreated rat and the anti-diabetic effect of the antagonist SSR240612

The involvement of kallikrein-kinin system in diabetes type I (insulitis)

A novel antithrombotic mechanism mediated by the receptors of the kallikrein/kinin and renin-angiotensin systems

Contact pathway of coagulation and inflammation

Physiologic activities of the contact activation system

Kinin B1 receptor: a potential therapeutic target in sepsis-induced vascular hyperpermeability

Kallikrein cleaves C3 and activates complement

Induction of complement C3a receptor responses by kallikrein-related peptidase 14

The terminal complement complex induces vascular leakage: in vitro and in vivo evidence

Platelet-activating factor and kinin-dependent vascular leakage as a novel functional activity of the soluble terminal complement complex

ACE2: angiotensin II/angiotensin-(1-7) balance in cardiac and renal injury

Emerging concepts in the diagnosis and treatment of patients with undifferentiated angioedema

Diagnosis and treatment of bradykinin-mediated angioedema: outcomes from an angioedema expert consensus meeting

Angioedema and emergency medicine: from pathophysiology to diagnosis and treatment

Nitric oxide mediates C5a-induced vasodilation in the small intestine

Type 2 diabetes mellitus: from a metabolic disorder to an inflammatory condition

Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes

Comorbid type 2 diabetes mellitus and hypertension exacerbates cognitive decline: evidence from a longitudinal study

The association between hypertension comorbidity and microvascular complications in type 2 diabetes patients: a nationwide cross-sectional study in Thailand

Hyperglycemiamediated oxidative stress increases pulmonary vascular permeability

Vascular complications in diabetes and their prevention

Hyperglycemia stimulates coagulation, whereas hyperinsulinemia impairs fibrinolysis in healthy humans

Interleukin-6 impairs the insulin signaling pathway, promoting production of nitric oxide in human umbilical vein endothelial cells

Diabetes and cardiovascular disease: the "common soil" hypothesis

IL-6 in diabetes and cardiovascular complications

Type 2 diabetes as an inflammatory cardiovascular disorder

Insulin resistance is a cardiovascular risk factor in humans

The origins and drivers of insulin resistance

Increased number of islet-associated macrophages in type 2 diabetes

Cytokines and abnormal glucose and lipid metabolism in type 2 diabetes

The role of macrophages in obesity-associated islet inflammation and β-cell abnormalities

Obesity induces a phenotypic switch in adipose tissue macrophage polarization

Low-grade inflammation, obesity, and diabetes

Regulation of adipose tissue inflammation by interleukin 6

Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice

Subcutaneous and visceral adipose tissue gene expression of serum adipokines that predict type 2 diabetes

Activation of AMP-activated protein kinase rapidly suppresses multiple pro-inflammatory pathways in adipocytes including IL-1 receptor-associated kinase-4 phosphorylation

In vivo JNK activation in pancreatic β-cells leads to glucose intolerance caused by insulin resistance in pancreas

The renin-angiotensin system in adipose tissue and its metabolic consequences during obesity

Adipose tissue renin-angiotensin-aldosterone system (RAAS) and progression of insulin resistance

Tyr612 and Tyr632 in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells

Regulation of endothelium-derived nitric oxide production by the protein kinase Akt

Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells

Vasoprotection by nitric oxide: mechanisms and therapeutic potential

Vasoprotective effects of nitric oxide in atherosclerosis

Endothelial dysfunction as a target for prevention of cardiovascular disease

The c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307

The vascular endothelium, a benign restrictive barrier? No! Role of nitric oxide in regulating insulin action

Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action

c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade

Hyperglycemia and hyperinsulinemia have additive effects on activation and proliferation of pancreatic stellate cells: possible explanation of islet-specific fibrosis in type 2 diabetes mellitus

Insulin promotes proliferation, survival, and invasion in endometrial carcinoma by activating the MEK/ERK pathway

Modulators of insulin action and their role in insulin resistance

The renin-angiotensin-aldosterone system, glucose metabolism and diabetes

Hyperinsulinemia: effect on cardiac mass/function, angiotensin II receptor expression, and insulin signaling pathways

The role of the reninangiotensin system in the development of insulin resistance in skeletal muscle

ANG II type I receptor antagonism improved nitric oxide production and enhanced eNOS and PKB/Akt expression in hearts from a rat model of insulin resistance

Renin-angiotensin-aldosterone system in diabetes and hypertension

Metabolic actions of angiotensin II and insulin: a microvascular endothelial balancing act

Association between insulin resistance and the development of cardiovascular disease

Insulin resistance and pancreatic β cell failure

Interleukin-6 regulates pancreatic α-cell mass expansion

Pancreatic β cell proliferation by intermittent hypoxia via up-regulation of Reg family genes and HGF gene

Interleukin-6 induces cellular insulin resistance in hepatocytes

Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells

Hyperglycemia induces monocytic release of interleukin-6 via induction of protein kinase C-α and-β

Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress

Interleukin-6 treatment induces beta-cell apoptosis via STAT-3-mediated nitric oxide production

The renin angiotensin system, oxidative stress and mitochondrial function in obesity and insulin resistance

Insulin action and insulin resistance in vascular endothelium

Role of advanced glycation end products (AGEs) and receptor for AGEs (RAGE) in vascular damage in diabetes

Diabetic vascular dysfunction: links to glucose-induced reductive stress and VEGF

Cellular death, reactive oxygen species (ROS) and diabetic complications

Microvascular permeability in diabetes and insulin resistance

Inhibition of NADPH oxidase prevents advanced glycation end product-mediated damage in diabetic nephropathy through a protein kinase C-α-dependent pathway

Hyperglycemia-induced oxidative stress induces apoptosis by inhibiting PI3-kinase/Akt and ERK1/2 MAPK mediated signaling pathway causing downregulation of 8-oxoG-DNA glycosylase levels in glial cells

The role of ERK1/2 in the development of diabetic cardiomyopathy

High-glucose stimulation increases reactive oxygen species production through the calcium and mitogen-activated protein kinase-mediated activation of mitochondrial fission

Acute and chronic hyperglycemia elicit JIP1/JNK-mediated endothelial vasodilator dysfunction of retinal arterioles

Hyperglycemia induces iNOS gene expression and consequent nitrosative stress via JNK activation

Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways

Chromatin decondensation and T cell hyperresponsiveness in diabetes-associated hyperglycemia

High glucose and hyperglycemic sera from type 2 diabetic patients impair DC differentiation by inducing ROS and activating Wnt/β-catenin and p38 MAPK

Hyperglycemia modulates redox, inflammatory and vasoactive markers through specific signaling pathways in cerebral endothelial cells: insights on insulin protective action

Mechanism of high glucose-induced angiotensin II production in rat vascular smooth muscle cells

Inhibition of MAPKmediated ACE expression by compound C66 prevents STZ-induced diabetic nephropathy

Hyperglycemia activates p53 and p53-regulated genes leading to myocyte cell death

High glucose up-regulates ADAM17 through HIF-1α in mesangial cells

ADAM17 and impaired endothelial insulin signaling in type 2 diabetes

Endothelial dysfunction: is there a hyperglycemia-induced imbalance of NOX and NOS?

Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes

Diabetesinduced reactive oxygen species: mechanism of their generation and role in renal injury

Effects of acute and chronic hyperglycemia on lung capillary permeability

Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: an update on glucose toxicity

Hyperglycemia: a prothrombotic factor?

Complement activation in patients with diabetic nephropathy

Hyperglycemia inhibits complement-mediated immunological control of S. aureus in a rat model of peritonitis

Association of the insulin resistance marker TyG index with the severity and mortality of COVID-19

Role of acid sphingomyelinase and IL-6 as mediators of endotoxininduced pulmonary vascular dysfunction

The varying faces of IL-6: from cardiac protection to cardiac failure

Roles of IL-6-gp130 signaling in vascular inflammation

Interleukin-6 causes endothelial barrier dysfunction via the protein kinase C pathway

Interleukin-6: from an inflammatory marker to a target for inflammatory diseases

Cytokine release syndrome in severe COVID-19

Different soluble forms of the interleukin-6 family signal transducer gp130 fine-tune the blockade of interleukin-6 trans-signaling

IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6

Interleukin-6 inhibits endothelial nitric oxide synthase activation and increases endothelial nitric oxide synthase binding to stabilized caveolin-1 in human vascular endothelial cells

Interleukin-6 modulation of intestinal epithelial tight junction permeability is mediated by JNK pathway activation of claudin-2 gene

C-Jun N-terminal kinase (JNK) inhibitor, SP600125, blocks interleukin (IL)-6-induced vascular endothelial growth factor (VEGF) production: cyclosporine A partially mimics this inhibitory effect

Interleukin-6 regulates ironrelated proteins through c-Jun N-terminal kinase activation in BV2 microglial cell lines

Interleukin-6 stimulates Akt and p38 MAPK phosphorylation and fibroblast migration in non-diabetic but not diabetic mice

Stress activated protein kinase p38 is involved in IL-6 induced transcriptional activation of STAT3

Protein kinases: mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance

Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle

Selective role of vinculin in contractile mechanisms of endothelial permeability

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Hypomethylation of interleukin-6 (IL-6) gene increases the risk of essential hypertension: a matched case-control study

Role of IL-6/JAK/STAT pathway in inducing vascular insulin resistance

Inflammation induced insulin resistance is associated with DNA methylation changes in vascular endothelial cells

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Tocilizumab treatment in COVID-19: a single center experience

Tocilizumab treatment in severe COVID-19 patients attenuates the inflammatory storm incited by monocyte centric immune interactions revealed by single-cell analysis

Cytokine release syndrome (CRS) of severe COVID-19 and interleukin-6 receptor (IL-6R) antagonist tocilizumab may be the key to reduce the mortality

Tocilizumab, an anti-IL-6 receptor antibody, to treat COVID-19-related respiratory failure: a case report

COVID-19 pandemic; transmembrane protease serine 2 (TMPRSS2) inhibitors as potential drugs

Nafamostat mesylate blocks activation of SARS-CoV-2: new treatment option for COVID-19

Identification of an existing Japanese pancreatitis drug, Nafamostat, which is expected to prevent the transmission of new coronavirus infection

Recent advances on plasmin inhibitors for the treatment of fibrinolysis-related disorders

Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis

Impact of angiotensin-converting enzyme inhibitors and statins on viral pneumonia

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Losartan attenuates microvascular permeability in mechanical ventilator-induced lung injury in diabetic mice

Rapid improvement of acute pulmonary edema with angiotensin converting enzyme inhibitor under hemodialysis in a patient with renovascular disease

Acquired angioedema induced by angiotensin-converting enzyme inhibitors-experience of a hospital-based allergy center

Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension

Renin-angiotensinaldosterone system blockers and the risk of Covid-19

Reninangiotensin-aldosterone system inhibitors and risk of Covid-19

Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy?

Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2

Complement as a target in COVID-19?

Complement-mediated thrombotic microangiopathy secondary to sepsisinduced disseminated intravascular coagulation successfully treated with eculizumab: a case report

A hypothesized role for dysregulated bradykinin signaling in covid-19 respiratory complications

Clinical characteristics and safety of plasma-derived C1-inhibitor therapy in children and adolescents with hereditary angioedemaa long-term survey

Pharming reports encouraging results from use of RUCONEST in COVID-19 patients

Tocilizumab: an updated review of its use in the treatment of rheumatoid arthritis and its application for other immune-mediated diseases

COVID-19: consider cytokine storm syndromes and immunosuppression

Negative impact of hyperglycemia on tocilizumab therapy in COVID-19 patients

SARS-CoV-2 and COVID-19: is interleukin-6 (IL-6) the'culprit lesion'of ARDS onset? What is there besides tocilizumab? SGP130Fc