Recent advances in the discovery and development of drugs targeting the kallikrein-kinin system.

BACKGROUND: The kallikrein-kinin system is a key regulatory cascade involved in blood pressure maintenance, hemostasis, inflammation and renal function. Currently, approved drugs remain limited to the rare disease hereditary angioedema. However, growing interest in this system is indicated by an increasing number of promising drug candidates for further indications. METHODS: To provide an overview of current drug development, a two-stage literature search was conducted between March and December 2023 to identify drug candidates with targets in the kallikrein-kinin system. First, drug candidates were identified using PubMed and Clinicaltrials.gov. Second, the latest publications/results for these compounds were searched in PubMed, Clinicaltrials.gov and Google Scholar. The findings were categorized by target, stage of development, and intended indication. RESULTS: The search identified 68 drugs, of which 10 are approved, 25 are in clinical development, and 33 in preclinical development. The three most studied indications included diabetic retinopathy, thromboprophylaxis and hereditary angioedema. The latter is still an indication for most of the drug candidates close to regulatory approval (3 out of 4). For the emerging indications, promising new drug candidates in clinical development are ixodes ricinus-contact phase inhibitor for thromboprophylaxis and RZ402 and THR-149 for the treatment of diabetic macular edema (all phase 2). CONCLUSION: The therapeutic impact of targeting the kallikrein-kinin system is no longer limited to the treatment of hereditary angioedema. Ongoing research on other diseases demonstrates the potential of therapeutic interventions targeting the kallikrein-kinin system and will provide further treatment options for patients in the future.

Kinin-kallikrein system: New perspectives in heart failure.

Heart failure (HF) is a pervasive clinical challenge characterized by compromised cardiac function and reduced quality of life. The kinin-kallikrein system (KSS), a multifaceted peptide cascade, has garnered substantial attention due to its potential role in HF. Through activation of B1 and/or B2 receptors and downstream signaling, kinins modulate various physiological processes, including inflammation, coagulation, pain, blood pressure control, and vascular permeability. Notably, aberrations in KKS components have been linked to HF risk. The elevation of vasodilatory bradykinin (BK) due to kallikrein activity reduces preload and afterload, while concurrently fostering sodium reabsorption inhibition. However, kallikrein's conversion of prorenin to renin leads to angiotensinsII upregulation, resulting in vasoconstriction and fluid retention, alongside increased immune cell activity that fuels inflammation and cardiac remodeling. Importantly, prolonged KKS activation resulting from volume overload and tissue stretch contributes to cardiac collagen loss. The conventional renin-angiotensin-aldosterone system (RAAS) inhibitors used in HF management may inadvertently intensify KKS activity, exacerbating collagen depletion and cardiac remodeling. It is crucial to balance the KKS's role in acute cardiac damage, which may temporarily enhance function and metabolic parameters against its detrimental long-term effects. Thus, KKS blockade emerges as a promising strategy to impede HF progression. By attenuating the link between immune system function and tissue damage, KKS inhibition can potentially reduce cardiac remodeling and alleviate HF symptoms. However, the nuanced roles of BK in various acute conditions necessitate further investigation into the sustained benefits of kallikrein inhibitors in patients with chronic HF.

The role of vasoactive peptides in skin homeostasis-focus on adiponectin and the kallikrein-kinin system.

Vasoactive peptides often serve a multitude of functions aside from their direct effects on vasodynamics. This article will review the existing literature on two vasoactive peptides and their involvement in skin homeostasis: adiponectin and-as the main representative of the kallikrein-kinin system-bradykinin. Adiponectin is the most abundantly expressed adipokine in the human organism, where it is mainly localized in fat depots including subcutaneous adipose tissue, from where adiponectin can exert paracrine effects. The involvement of adiponectin in skin homeostasis is supported by a number of studies reporting the effects of adiponectin in isolated human keratinocytes, sebocytes, fibroblasts, melanocytes, and immune cells. Regarding skin pathology, the potential involvement of adiponectin in psoriasis, atopic dermatitis, scleroderma, keloid, and melanogenesis is discussed in this article. The kallikrein-kinin system is composed of a variety of enzymes and peptides, most of which have been identified to be expressed in the skin. This also includes the expression of bradykinin receptors on most skin cells. Bradykinin is one of the very few hormones that is targeted by treatment in routine clinical use in dermatology-in this case for the treatment of hereditary angioedema. The potential involvement of bradykinin in wound healing, psoriasis, and melanoma is further discussed in this article. This review concludes with a call for additional preclinical and clinical studies to further explore the therapeutic potential of adiponectin supplementation (for psoriasis, atopic dermatitis, wound healing, scleroderma, and keloid) or pharmacological interference with the kallikrein-kinin system (for wound healing, psoriasis, and melanoma).

Quantitative detection of RAS and KKS peptides in COVID-19 patient serum by stable isotope dimethyl labeling LC-MS.

Angiotensin and kinin metabolic pathways are reported to be altered by many diseases, including COVID-19. Monitoring levels of these peptide metabolites is important for understanding mechanisms of disease processes. In this paper, we report dimethyl labeling of amines in peptides by addition of formaldehyde to samples and deutero-formaldehyde to internal standards to generate nearly identical isotopic standards with 4 m/z units larger per amine group than the corresponding analyte. We apply this approach to rapid, multiplexed, absolute LC-MS/MS quantitation of renin angiotensin system (RAS) and kallikrein-kinin system (KKS) peptides in human blood serum. Limits of detection (LODs) were obtained in the low pg mL-1 range with 3 orders of magnitude dynamic ranges, appropriate for determinations of normal and elevated levels of the target peptides in blood serum and plasma. Accuracy is within ±15% at concentrations above the limit of quantitation, as validated by spike-recovery in serum samples. Applicability was demonstrated by measuring RAS and KKS peptides in serum from COVID-19 patients, but is extendable to any class of peptides or other small molecules bearing reactive -NH2 groups.

Pharmacological suppression of the kallikrein kinin system with KVD900: An orally available plasma kallikrein inhibitor for the on-demand treatment of hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disease that leads to recurrent episodes of swelling and pain caused by uncontrolled plasma kallikrein (PKa) activity. Current guidelines recommend ready availability of on-demand HAE treatments that can be administered early upon attack onset. This report describes the pharmacological and pharmacodynamic properties of the novel oral small-molecule PKa inhibitor KVD900 as a potential on-demand treatment for HAE. METHODS: Pharmacological properties of KVD900 on PKa and closely related serine proteases were characterized using kinetic fluorogenic substrate activity assays. Effects of KVD900 on PKa activity and kallikrein kinin system activation in whole plasma were measured in the presence of dextran sulphate (DXS)-stimulation using a fluorogenic substrate and capillary immunoassays to quantify high molecular weight kininogen (HK), plasma prekallikrein and Factor XII cleavage. Pharmacodynamic effects of orally administered KVD900 were characterized in plasma samples from six healthy controls in a first in human phase 1 clinical trial and from 12 participants with HAE in a phase 2 clinical trial. RESULTS: KVD900 is a selective, competitive and reversible inhibitor of human PKa enzyme with a Ki of 3.02 nM. The association constant (Kon ) of KVD900 for PKa is >10 × 106  M-1  s-1 . Oral administration of KVD900 in a first-in-human clinical trial achieved rapid and near complete inhibition of DXS-stimulated PKa enzyme activity and HK cleavage and reduced plasma prekallikrein and Factor XII activation in plasma. In individuals with HAE, orally administered KVD900 inhibited DXS-stimulated PKa activity in plasma by ≥95% from 45 min to at least 4 h post-dose and provided rapid protection of HK from cleavage. CONCLUSION: KVD900 is a fast-acting oral PKa inhibitor that rapidly inhibits PKa activity, kallikrein kinin system activation and HK cleavage in plasma. On-demand administration of KVD900 may provide an opportunity to halt the generation of bradykinin and reverse HAE attacks.

Dysregulated Bradykinin: Mystery in the Pathogenesis of COVID-19.

The COVID-19 pandemic is rapidly spreading, and health care systems are being overwhelmed with the huge number of cases, with a good number of cases requiring intensive care. It has become imperative to develop safe and effective treatment strategies to improve survival. In this regard, understanding the pathogenesis of COVID-19 is highly important. Many hypotheses have been proposed, including the ACE/angiotensin-II/angiotensin receptor 1 pathway, the complement pathway, and the angiotensin-converting enzyme 2/mitochondrial assembly receptor (ACE2/MasR) pathway. SARS-CoV-2 binds to the ACE2 on the cell surface, downregulating the ACE2, and thus impairs the inactivation of bradykinin and des-Arg9-bradykinin. Bradykinin, a linear nonapeptide, is extensively distributed in plasma and different tissues. Kininogens in plasma and tissue are the main sources of the two vasoactive peptides called bradykinin and kallidin. However, the role of the dysregulated bradykinin pathway is less explored in the pathogenesis of COVID-19. Understanding the pathogenesis of COVID-19 is crucial for the development of new effective treatment approaches which interfere with these pathways. In this review, we have tried to explore the interaction between SARS-CoV-2, ACE2, bradykinin, and its metabolite des-Arg9-bradykinin in the pathogenesis of COVID-19.

Ameliorative Effect of Dabigatran on CFA-Induced Rheumatoid Arthritis via Modulating Kallikrein-Kinin System in Rats.

Rheumatoid arthritis is an autoimmune disease that affects joints, leading to swelling, inflammation, and dysfunction in the joints. Recently, research efforts have been focused on finding novel curative approaches for rheumatoid arthritis, as current therapies are associated with adverse effects. Here, we examined the effectiveness of dabigatran, the antithrombotic agent, in treating complete Freund's adjuvant (CFA)-induced arthritis in rats. Subcutaneous injection of a single 0.3 mL dosage of CFA into the rat's hind leg planter surface resulted in articular surface deformities, reduced cartilage thickness, loss of intercellular matrix, and inflammatory cell infiltration. There were also increased levels of the Anti-cyclic citrullinated peptide antibody (ACPA), oxidative stress, and tissue Receptor activator of nuclear factor-kappa B ligand (RANKL). Proteins of the kallikrein-kinin system (KKS) were also elevated. The inhibitory effects of dabigatran on thrombin led to a subsequent inhibition of KKS and reduced Toll-like receptor 4 (TLR4) expression. These effects also decreased RANKL levels and showed anti-inflammatory and antioxidant effects. Therefore, dabigatran could be a novel therapeutic strategy for arthritis.

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

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.

Targeted LC-MS/MS platform for the comprehensive determination of peptides in the kallikrein-kinin system.

The kallikrein-kinin system (KKS) is involved in many physiological and pathophysiological processes and is assumed to be connected to the development of clinical symptoms of angioedema or COVID-19, among other diseases. However, despite its diverse role in the regulation of physiological and pathophysiological functions, knowledge about the KKS in vivo remains limited. The short half-lives of kinins, their low abundance and structural similarities and the artificial generation of the kinin bradykinin greatly hinder reliable and accurate determination of kinin levels in plasma. To address these issues, a sensitive LC-MS/MS platform for the comprehensive and simultaneous determination of the four active kinins bradykinin, kallidin, des-Arg(9)-bradykinin and des-Arg(10)-kallidin and their major metabolites bradykinin 2-9, bradykinin 1-7 and bradykinin 1-5 was developed. This platform was validated according to the bioanalytical guideline of the US Food and Drug Administration regarding linearity, accuracy, precision, sensitivity, carry-over, recovery, parallelism, matrix effects and stability in plasma of healthy volunteers. The validated platform encompassed a broad calibration curve range from 2.0-15.3 pg/mL (depending on the kinin) up to 1000 pg/mL, covering the expected concentrations in disease states. No source-dependent matrix effects were identified, and suitable stability of the analytes in plasma was observed. The applicability of the developed platform was proven by the determination of endogenous levels in healthy volunteers, whose plasma kinin levels were successfully detected in the low pg/mL range. The established platform facilitates the investigation of kinin-mediated diseases (e.g. angioedema, COVID-19) and enables the assessment of the impact of altered enzyme activities on the formation or degradation of kinins.

Treatment of Hereditary Angioedema.

Hereditary angioedema due to C1-esterase inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease. In the last decade, new drugs and new indications for old drugs have played a role in the management of C1-INH-HAE. This review examines current therapy for C1-INH-HAE and provides a brief summary of drugs that are under development. Increased knowledge of the pathophysiology of C1-INH-HAE has been crucial for advances in the field, with inhibition of the kallikrein-kinin system (plasma kallikrein, activated factor XII) as a key area in the discovery of new drugs, some of which are already marketed for treatment of C1-INH-HAE. Pharmacological treatment is based on 3 pillars: treatment of acute angioedema attacks (on-demand treatment), short-term (preprocedure) prophylaxis, and long-term prophylaxis. The 4 drugs that are currently available for the treatment of acute angioedema attacks (purified plasma-derived human C1 esterase inhibitor concentrate, icatibant acetate, ecallantide, recombinant human C1 esterase inhibitor) are all authorized for self-administration, except ecallantide. Purified plasma-derived human C1 esterase inhibitor concentrate is the treatment of choice for short-term prophylaxis. Tranexamic acid, danazol, intravenous and subcutaneous nanofiltered purified plasma-derived human C1 esterase inhibitor concentrate, and lanadelumab can be used for long-term prophylaxis. New drugs are being investigated, mainly as long-term prophylaxis, and are aimed at blocking the kallikrein-kinin system by means of antiprekallikrein, antikallikrein, and anti-activated FXII action.

Role of the Renin-Angiotensin-Aldosterone and Kinin-Kallikrein Systems in the Cardiovascular Complications of COVID-19 and Long COVID.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the virus responsible for the COVID-19 pandemic. Patients may present as asymptomatic or demonstrate mild to severe and life-threatening symptoms. Although COVID-19 has a respiratory focus, there are major cardiovascular complications (CVCs) associated with infection. The reported CVCs include myocarditis, heart failure, arrhythmias, thromboembolism and blood pressure abnormalities. These occur, in part, because of dysregulation of the Renin-Angiotensin-Aldosterone System (RAAS) and Kinin-Kallikrein System (KKS). A major route by which SARS-CoV-2 gains cellular entry is via the docking of the viral spike (S) protein to the membrane-bound angiotensin converting enzyme 2 (ACE2). The roles of ACE2 within the cardiovascular and immune systems are vital to ensure homeostasis. The key routes for the development of CVCs and the recently described long COVID have been hypothesised as the direct consequences of the viral S protein/ACE2 axis, downregulation of ACE2 and the resulting damage inflicted by the immune response. Here, we review the impact of COVID-19 on the cardiovascular system, the mechanisms by which dysregulation of the RAAS and KKS can occur following virus infection and the future implications for pharmacological therapies.

Identification of Human Kinin-Forming Enzyme Inhibitors from Medicinal Herbs.

The goal of this study was to assess the pharmacological effects of black tea (Camellia sinensis var. assamica) water extract on human kinin-forming enzymes in vitro. Tea is a highly consumed beverage in the world. Factor XII (FXII, Hageman factor)-independent- and -dependent activation of prekallikrein to kallikrein leads to the liberation of bradykinin (BK) from high-molecular-weight kininogen (HK). The excessive BK production causes vascular endothelial and nonvascular smooth muscle cell permeability, leading to angioedema. The prevalence of angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema appears to be through BK. Both histamine and BK are potent inflammatory mediators. However, the treatments for histamine-mediated angioedema are unsuitable for BK-mediated angioedema. We hypothesized that long-term consumption of tea would reduce bradykinin-dependent processes within the systemic and pulmonary vasculature, independent of the anti-inflammatory actions of polyphenols. A purified fraction of the black tea water extract inhibited both kallikrein and activated FXII. The black tea water extracts inhibited factor XII-induced cell migration and inhibited the production of kallikrein on the endothelial cell line. We compared the inhibitory effects of the black tea water extract and twenty-three well-known anti-inflammatory medicinal herbs, in inhibiting both kallikrein and FXII. Surprisingly, arjunglucoside II specifically inhibited the activated factor XII (FXIIa), but not the kallikrein and the activated factor XI. Taken together, the black tea water extract exerts its anti-inflammatory effects, in part, by inhibiting kallikrein and activated FXII, which are part of the plasma kallikrein-kinin system (KKS), and by decreasing BK production. The inhibition of kallikrein and activated FXII represents a unique polyphenol-independent anti-inflammatory mechanism of action for the black tea.

Carbon-Coated Stent and the Role of the Kallikrein-Kinin System in Peripheral Angioplasty.

OBJECTIVE: The purpose of this study was to investigate the clinical evolution of patients treated with carbon-coated stent, as well as its patency and the inflammatory response triggered by this process through the quantification of serum elements of the kallikrein-kinin system (KKS). METHODS: This was a single-center prospective study with 27 patients with peripheral artery disease (PAD) who required percutaneous transluminal angioplasty and stenting of the iliacofemoropopliteal segment using carbon-coated stent grafts (carbostents). The blood concentrations of the total and kininogen fractions were evaluated using immunoenzymatic methods. Plasma kallikrein levels were assessed by the colorimetric method and tissue kallikrein levels were evaluated by the spectrophotometric method. The activity of kininase II was measured by -fluorometric analysis. RESULTS: Of the 27 patients who completed the 6 months of the study (11 iliac territory, 16 femoropopliteal territory), only one experienced restenosis (3.7%) (femoropopliteal segment) and no patient had occlusion (96.3% of patency). In 1 year, four patients were lost to follow-up and all 23 patients evaluated maintained stent patency, except for the patient who had restenosis throughout the first 6 months. We report complete (100%) member salvage in 12 months of follow-up. The activity levels of high- and low-molecular-weight kininogens decreased significantly over time (before vs. 24 h, p < 0.01; before vs. 6 months, p < 0.001, and before vs. 24 h, p < 0.01; before vs. 6 months, p < 0.001; 24 h vs. 6 months, p < 0.001, respectively). Patients also had significantly lower levels of plasma and tissue kallikrein (before vs. 24 h, p < 0.001; before vs. 6 months, p < 0.001, and before vs. 24 h, p < 0.01; before vs. 6 months, p < 0.05, respectively). There was a significant increase in the enzymatic activity of kininase II at 24 h and after 6 months compared to the pre-treatment control (p < 0.001). CONCLUSION: Our early experience shows that the use of carbon-coated stents in PAD appears to be safe, with low rates of early restenosis (3.7% in the first 6 months and 5% in the 12 months of follow-up). We concluded that KKS was involved in the inflammatory response caused by the placement of carbon-coated stents.

Neutrophils engage the kallikrein-kinin system to open up the endothelial barrier in acute inflammation.

Neutrophil recruitment and plasma exudation are key elements in the immune response to injury or infection. Activated neutrophils stimulate opening of the endothelial barrier; however, the underlying mechanisms have remained largely unknown. In this study, we identified a pivotal role of the proinflammatory kallikrein-kinin system and consequent formation of bradykinin in neutrophil-evoked vascular leak. In mouse and hamster models of acute inflammation, inhibitors of bradykinin generation, and signaling markedly reduced plasma exudation in response to chemoattractant activation of neutrophils. The neutrophil-driven leak was likewise suppressed in mice deficient in either the bradykinin B2 receptor or factor XII (initiator of the kallikrein-kinin system). In human endothelial cell monolayers, material secreted from activated neutrophils induced cytoskeletal rearrangement, leading to paracellular gap formation in a bradykinin-dependent manner. As a mechanistic basis, we found that a neutrophil-derived heparin-binding protein (HBP/azurocidin) displaced the bradykinin precursor high-molecular-weight kininogen from endothelial cells, thereby enabling proteolytic processing of kininogen into bradykinin by neutrophil and plasma proteases. These data provide novel insight into the signaling pathway by which neutrophils open up the endothelial barrier and identify the kallikrein-kinin system as a target for therapeutic interventions in acute inflammatory reactions.-Kenne, E., Rasmuson, J., Renné, T., Vieira, M. L., Müller-Esterl, W., Herwald, H., Lindbom, L. Neutrophils engage the kallikrein-kinin system to open up the endothelial barrier in acute inflammation.

Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo.

Activated mast cells trigger edema in allergic and inflammatory disease. We report a paracrine mechanism by which mast cell-released heparin increases vascular permeability in vivo. Heparin activated the protease factor XII, which initiates bradykinin formation in plasma. Targeting factor XII or kinin B2 receptors abolished heparin-triggered leukocyte-endothelium adhesion and interfered with a mast cell-driven drop in blood pressure in rodents. Intravital laser scanning microscopy and tracer measurements showed heparin-driven fluid extravasation in mouse skin microvessels. Ablation of factor XII or kinin B2 receptors abolished heparin-induced skin edema and protected mice from allergen-activated mast cell-driven leakage. In contrast, heparin and activated mast cells induced excessive edema in mice deficient in the major inhibitor of factor XII, C1 esterase inhibitor. Allergen exposure triggered edema attacks in hereditary angioedema patients, lacking C1 esterase inhibitor. The data indicate that heparin-initiated bradykinin formation plays a fundamental role in mast cell-mediated diseases.

Novel anti-thrombotic mechanisms mediated by Mas receptor as result of balanced activities between the kallikrein/kinin and the renin-angiotensin systems.

The risk of thrombosis, a globally growing challenge and a major cause of death, is influenced by various factors in the intravascular coagulation, vessel wall, and cellular systems. Among the contributors to thrombosis, the contact activation system and the kallikrein/kinin system, two overlapping plasma proteolytic systems that are often considered as synonymous, regulate thrombosis from different aspects. On one hand, components of the contact activation system such as factor XII initiates activation of the coagulation proteins promoting thrombus formation on artificial surfaces through factor XI- and possibly prekallikrein-mediated intrinsic coagulation. On the other hand, physiological activation of plasma prekallikrein in the kallikrein/kinin system on endothelial cells liberates bradykinin from associated high-molecular-weight kininogen to stimulate the constitutive bradykinin B2 receptor to generate nitric oxide and prostacyclin to induce vasodilation and counterbalance angiotensin II signaling from the renin-angiotensin system which stimulates vasoconstriction. In addition to vascular tone regulation, this interaction between the kallikrein/kinin and renin-angiotensin systems has a thrombo-regulatory role independent of the contact pathway. At the level of the G-protein coupled receptors of these systems, defective bradykinin signaling due to attenuated bradykinin formation and/or decreased B2 receptor expression, as seen in murine prekallikrein and B2 receptor null mice, respectively, leads to compensatory overexpressed Mas, the receptor for angiotensin-(1-7) of the renin-angiotensin system. Mas stimulation and/or its increased expression contributes to maintaining a healthy vascular homeostasis by generating graded elevation of plasma prostacyclin which reduces thrombosis through two independent pathways: (1) increasing the vasoprotective transcription factor Sirtuin 1 to suppress tissue factor expression, and (2) inhibiting platelet activation. This review will summarize the recent advances in this field that support these understandings. Appreciating these subtle mechanisms help to develop novel anti-thrombotic strategies by targeting the vascular receptors in the renin-angiotensin and the kallikrein/kinin systems to maintain healthy vascular homeostasis.

Exogenous pancreatic kininogenase protects against renal fibrosis in rat model of unilateral ureteral obstruction.

Tissue kallikrein has protective function against various types of injury. In this study, we investigated whether exogenous pancreatic kininogenase (PK) conferred renoprotection in a rat model of unilateral ureteral obstruction (UUO) and H2O2-treated HK-2 cells in vitro. SD rats were subjected to UUO surgery, then PK (7.2 U/g per day, ip) was administered for 7 or 14 days. After the treatment, rats were euthanized; the obstructed kidneys were harvested for further examination. We found that PK administration significantly attenuated interstitial inflammation and fibrosis, and downregulated the expression of proinflammatory (MCP-1, TLR-2, and OPN) and profibrotic (TGF-ß1 and CTGF) cytokines in obstructed kidney. UUO-induced oxidative stress, closely associated with excessive apoptotic cell death and autophagy via PI3K/AKT/FoxO1a signaling, which were abolished by PK administration. We further showed that PK administration increased the expression of bradykinin receptors 1 and 2 (B1R and B2R) mRNA and the production of NO and cAMP in kidney tissues. Coadministration with either B1R antagonist (des-Arg9-[Leu8]-bradykinin) or B2R antagonist (icatibant) abrogated the renoprotective effects of PK, and reduced the levels of NO and cAMP in obstructed kidney. In H2O2-treated HK-2 cells, addition of PK (6 pg/mL) significantly decreased ROS production, regulated the expression of oxidant and antioxidant enzymes, suppressed the expression of TGF-ß1 and MCP-1, and inhibited cell apoptosis. Our data demonstrate that PK treatment protects against the progression of renal fibrosis in obstructed kidneys.

Emerging Mechanisms of Pulmonary Vasoconstriction in SARS-CoV-2-Induced Acute Respiratory Distress Syndrome (ARDS) and Potential Therapeutic Targets.

The 1918 influenza killed approximately 50 million people in a few short years, and now, the world is facing another pandemic. In December 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an international outbreak of a respiratory illness termed coronavirus disease 2019 (COVID-19) and rapidly spread to cause the worst pandemic since 1918. Recent clinical reports highlight an atypical presentation of acute respiratory distress syndrome (ARDS) in COVID-19 patients characterized by severe hypoxemia, an imbalance of the renin-angiotensin system, an increase in thrombogenic processes, and a cytokine release storm. These processes not only exacerbate lung injury but can also promote pulmonary vascular remodeling and vasoconstriction, which are hallmarks of pulmonary hypertension (PH). PH is a complication of ARDS that has received little attention; thus, we hypothesize that PH in COVID-19-induced ARDS represents an important target for disease amelioration. The mechanisms that can promote PH following SARS-CoV-2 infection are described. In this review article, we outline emerging mechanisms of pulmonary vascular dysfunction and outline potential treatment options that have been clinically tested.

A Role of Inflammation and Immunity in Essential Hypertension-Modeled and Analyzed Using Petri Nets.

Recent studies have shown that the innate and adaptive immune system, together with low-grade inflammation, may play an important role in essential hypertension. In this work, to verify the importance of selected factors for the development of essential hypertension, we created a Petri net-based model and analyzed it. The analysis was based mainly on t-invariants, knockouts of selected fragments of the net and its simulations. The blockade of the renin-angiotensin (RAA) system revealed that the most significant effect on the emergence of essential hypertension has RAA activation. This blockade affects: (1) the formation of angiotensin II, (2) inflammatory process (by influencing C-reactive protein (CRP)), (3) the initiation of blood coagulation, (4) bradykinin generation via the kallikrein-kinin system, (5) activation of lymphocytes in hypertension, (6) the participation of TNF alpha in the activation of the acute phase response, and (7) activation of NADPH oxidase-a key enzyme of oxidative stress. On the other hand, we found that the blockade of the activation of the RAA system may not eliminate hypertension that can occur due to disturbances associated with the osmotically independent binding of Na in the interstitium. Moreover, we revealed that inflammation alone is not enough to trigger primary hypertension, but it can coexist with it. We believe that our research may contribute to a better understanding of the pathology of hypertension. It can help identify potential subprocesses, which blocking will allow better control of essential hypertension.