The role of kallikrein-kinin and renin-angiotensin systems in COVID-19 infection

Carvalho, Patricia Ribeiro de; Sirois, Pierré; Fernandes, Patrícia Dias

doi:10.1016/j.peptides.2020.170428

Cited by 28 publications

(36 citation statements)

References 91 publications

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“…The kallikrein-kinin system is indeed linked with the contact pathway of coagulation, 28 but its true contribution can only be interpretated as being one component of a complex network of multiple downstream pathways within the coagulation system, the fibrinolytic system, the renin-angiotensin system, and the complement system. 2,26,29,30 Here, the role of thrombin-thrombomodulin as a central 'switch' between a pro-and antithromboinflammatory reaction, and the importance of the activated protein C pathway in regulating inflammation and thrombosis in severe inflammatory response syndrome, have been well-studied. 31 In this regard, neutrophils emerged as potential promotors of thromboinflammation in COVID-19, as their numbers are increased in bronchoalveolar lavage fluid of COVID-19 patients, 17 and their interconnection with the kallikrein-kinin system has been postulated before.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of the kallikrein-kinin system in bronchoalveolar lavage fluid of patients with severe COVID-19

et al. 2022

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Section: Discussionmentioning

confidence: 99%

Dysregulation of the kallikrein-kinin system in bronchoalveolar lavage fluid of patients with severe COVID-19

et al. 2022

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“…These aspects can directly link the plasma leakage events to the KKS activation (Figure 4). In addition to its essential role in RAAS, downregulation of ACE2, which can degrade DABK and lys-DABK, promotes the increasing of these hormones that, by binding B1R [65], can trigger the increase in vascular permeability and nitric oxide (NO) and cytokines' secretion [68][69][70].…”

Section: Mast Cell Degranulation and The Role Of Its Mediators In The...mentioning

confidence: 99%

“…A significant amount of ACE2 is lost during viral infection when the viral Sspike subunits bind with ACE2 receptor intervenes in the synthesis of a protein complex. A Transmembrane Serine Protease 2 (TMPRSS2) and furin, constitutively present in the plasma membrane of host cells, cleave the S-spike subunits into S1 and S2, allowing membrane fusion and insertion of viral RNA [65], causing a loss of ACE2 function. In an eventual absence of these surface enzymes, the virion particle can infect the host cell via endocytosis, along with ACE2 itself [66,67].…”

Section: Mast Cell Degranulation and The Role Of Its Mediators In The...mentioning

confidence: 99%

COVID-19 and Lung Mast Cells: The Kallikrein–Kinin Activation Pathway

Nagashima

Dutra

Arantes

et al. 2022

IJMS

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Mast cells (MCs) have relevant participation in inflammatory and vascular hyperpermeability events, responsible for the action of the kallikrein–kinin system (KKS), that affect patients inflicted by the severe form of COVID-19. Given a higher number of activated MCs present in COVID-19 patients and their association with vascular hyperpermeability events, we investigated the factors that lead to the activation and degranulation of these cells and their harmful effects on the alveolar septum environment provided by the action of its mediators. Therefore, the pyroptotic processes throughout caspase-1 (CASP-1) and alarmin interleukin-33 (IL-33) secretion were investigated, along with the immunoexpression of angiotensin-converting enzyme 2 (ACE2), bradykinin receptor B1 (B1R) and bradykinin receptor B2 (B2R) on post-mortem lung samples from 24 patients affected by COVID-19. The results were compared to 10 patients affected by H1N1pdm09 and 11 control patients. As a result of the inflammatory processes induced by SARS-CoV-2, the activation by immunoglobulin E (IgE) and degranulation of tryptase, as well as Toluidine Blue metachromatic (TB)-stained MCs of the interstitial and perivascular regions of the same groups were also counted. An increased immunoexpression of the tissue biomarkers CASP-1, IL-33, ACE2, B1R and B2R was observed in the alveolar septum of the COVID-19 patients, associated with a higher density of IgE+ MCs, tryptase+ MCs and TB-stained MCs, in addition to the presence of intra-alveolar edema. These findings suggest the direct correlation of MCs with vascular hyperpermeability, edema and diffuse alveolar damage (DAD) events that affect patients with a severe form of this disease. The role of KKS activation in events involving the exacerbated increase in vascular permeability and its direct link with the conditions that precede intra-alveolar edema, and the consequent DAD, is evidenced. Therapy with drugs that inhibit the activation/degranulation of MCs can prevent the worsening of the prognosis and provide a better outcome for the patient.

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“…Furthermore, ACE2 regulates the Kallikrein Kinin System (KKS). In this regards, after producing kinin from bradykininogens, this metabolite acts on both B1 and B2 receptors to induce inflammation and increase vascular permeability [14,19,20]. The most important agonist of B1 receptor is a bradykinin metabolite, i.e., [des-Arg9]-bradykinin (desArg9-BK), which is cleaved by ACE2.…”

Section: Renal Manifestationsmentioning

confidence: 99%

Renal, cardiac, neurological, cutaneous and coagulopathic long-term manifestations of COVID-19 after recovery; A review

et al. 2022

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the novel global coronavirus (COVID-19) disease outbreak. Its pathogenesis is mostly located in the respiratory tract. However, other organs are also affected. Hence, realizing how such a complex disturbance affects patients after recovery is crucial. Regarding the significance of control of COVID-19-related complications after recovery, the current study was designed to review the cellular and molecular mechanisms linking COVID-19 to significant long-term signs including renal and cardiac complications, cutaneous and neurological manifestations, as well as blood coagulation disorders. This virus can directly influence on the cells through Angiotensin converting enzyme 2 (ACE-2) to induce cytokine storm. Acute release of Interleukin-1 (IL1), IL6 and plasminogen activator inhibitor (PAI-1) have been related to elevating risk of heart failure. Also, inflammatory cytokines like IL-8 and Tumor necrosis factor-α (TNF-α) cause the secretion of von Willebrand factor (VWF) from human endothelial cells and then VWF binds to Neutrophil extracellular traps (NETs) to induce thrombosis. On the other hand, the virus can damage the blood-brain barrier by increasing its permeability and subsequently enters into the central nervous system (CNS) and the systemic circulation. Furthermore, SARS-induced ACE2-deficiency decreases [des-Arg9]bradykinin (desArg9-BK) degradation in kidneys to induce inflammation, thrombotic problems, fibrosis and necrosis. Notably, the angiotensin II-angiotensin II type 1 receptor (ANGII-AT1R) binding causes an increase in aldosterone and mineralocorticoid receptors on the surface of dendritic cells (DC) cells, leading to recalling macrophage and monocyte into inflammatory sites of skin. In conclusions, all the pathways play a key role in the pathogenesis of these disturbances. Nevertheless, more investigations are necessary to determine more pathogenetic mechanisms of the virus.

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The role of kallikrein-kinin and renin-angiotensin systems in COVID-19 infection

Abstract: Graphical abstract

Cited by 28 publications

References 91 publications

Dysregulation of the kallikrein-kinin system in bronchoalveolar lavage fluid of patients with severe COVID-19

Dysregulation of the kallikrein-kinin system in bronchoalveolar lavage fluid of patients with severe COVID-19

COVID-19 and Lung Mast Cells: The Kallikrein–Kinin Activation Pathway

Renal, cardiac, neurological, cutaneous and coagulopathic long-term manifestations of COVID-19 after recovery; A review

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