ACE2 Receptor-Targeted Inhaled Nanoemulsions Inhibit SARS-CoV-2 and Attenuate Inflammatory Responses.

Three kinds of coronaviruses are highly pathogenic to humans, and two of them mainly infect humans through Angiotensin-converting enzyme 2 （ACE2）receptors. Therefore, specifically blocking ACE2 binding at the interface with the receptor-binding domain is promising to achieve both preventive and therapeutic effects of coronaviruses. Alternatively, drug-targeted delivery based on ACE2 receptors can further improve the efficacy and safety of inhalation drugs. Here, these two approaches are innovatively combined by designing a nanoemulsion (NE) drug delivery system (termed NE-AYQ) for inhalation that targets binding to ACE2 receptors. This inhalation-delivered remdesivir nanoemulsion (termed RDSV-NE-AYQ) effectively inhibits the infection of target cells by both wild-type and mutant viruses. The RDSV-NE-AYQ strongly inhibits Severe acute respiratory syndrome coronavirus 2 at two dimensions: they not only block the binding of the virus to host cells at the cell surface but also restrict virus replication intracellularly. Furthermore, in the mouse model of acute lung injury, the inhaled drug delivery system loaded with anti-inflammatory drugs (TPCA-1-NE-AYQ) can significantly alleviate the lung tissue injury of mice. This smart combination provides a new choice for dealing with possible emergencies in the future and for the rapid development of inhaled drugs for the treatment of respiratory diseases.

Heparin-Induced Allosteric Changes in SARS-CoV-2 Spike Protein Facilitate ACE2 Binding and Viral Entry.

Understanding the entry of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) into host cells is crucial in the battle against COVID-19. Using atomic force microscopy (AFM), we probed the interaction between the virus's spike protein and heparan sulfate (HS) as a potential attachment factor. Our AFM studies revealed a moderate-affinity interaction between the spike protein and HS on both model surfaces and living cells, highlighting HS's role in early viral attachment. Remarkably, we observed an interplay between HS and the host cell receptor angiotensin-converting enzyme 2 (ACE2), with HS engagement resulting in enhanced ACE2 binding and subsequent viral entry. Our research furthers our understanding of SARS-CoV-2 infection mechanisms and reveals potential interventions targeting viral entry. These insights are valuable as we navigate the evolving landscape of viral threats and seek effective strategies to combat emerging infectious diseases.

The intrarenal renin-angiotensin system in hypertension: insights from mathematical modelling.

The renin-angiotensin system (RAS) plays a pivotal role in the maintenance of volume homeostasis and blood pressure. In addition to the well-studied systemic RAS, local RAS have been documented in various tissues, including the kidney. Given the role of the intrarenal RAS in the pathogenesis of hypertension, a role established via various pharmacologic and genetic studies, substantial efforts have been made to unravel the processes that govern intrarenal RAS activity. In particular, several mechanisms have been proposed to explain the rise in intrarenal angiotensin II (Ang II) that accompanies Ang II infusion, including increased angiotensin type 1 receptor (AT1R)-mediated uptake of Ang II and enhanced intrarenal Ang II production. However, experimentally isolating their contribution to the intrarenal accumulation of Ang II in Ang II-induced hypertension is challenging, given that they are fundamentally connected. Computational modelling is advantageous because the feedback underlying each mechanism can be removed and the effect on intrarenal Ang II can be studied. In this work, the mechanisms governing the intrarenal accumulation of Ang II during Ang II infusion experiments are delineated and the role of the intrarenal RAS in Ang II-induced hypertension is studied. To accomplish this, a compartmental ODE model of the systemic and intrarenal RAS is developed and Ang II infusion experiments are simulated. Simulations indicate that AT1R-mediated uptake of Ang II is the primary mechanism by which Ang II accumulates in the kidney during Ang II infusion. Enhanced local Ang II production is unnecessary. The results demonstrate the role of the intrarenal RAS in the pathogenesis of Ang II-induced hypertension and consequently, clinical hypertension associated with an overactive RAS.

Potential use of renin-angiotensin-aldosterone system inhibitors to reduce COVID-19 severity.

SARS-CoV-2 infection and its clinical manifestations (COVID-19) quickly evolved to a pandemic and a global public health emergency. The limited effectivity of available treatments aimed at reducing virus replication and the lessons learned from other coronavirus infections (SARS-CoV-1 or NL63) that share the internalization process of SARS-CoV-2, led us to revisit the COVID-19 pathogenesis and potential treatments. Virus protein S binds to the angiotensin-converting enzyme 2 (ACE2) initiating the internalization process. Endosome formation removes ACE2 from the cellular membrane preventing its counter-regulative effect mediated by the metabolism of angiotensin II to angiotensin (1-7). Internalized virus-ACE2 complexes have been identified for these coronaviruses. SARS-CoV-2 presents the highest affinity for ACE2 and produces the most severe symptoms. Assuming ACE2 internalization is the trigger for COVID-19 pathogenesis, accumulation of angiotensin II can be viewed as the potential cause of symptoms. Angiotensin II is a strong vasoconstrictor, but has also important roles in hypertrophy, inflammation, remodeling, and apoptosis. Higher levels of ACE2 in the lungs explain the acute respiratory distress syndrome as primary symptoms. Most of the described findings and clinical manifestations of COVID-19, including increased interleukin levels, endothelial inflammation, hypercoagulability, myocarditis, dysgeusia, inflammatory neuropathies, epileptic seizures and memory disorders can be explained by excessive angiotensin II levels. Several meta-analyses have demonstrated that previous use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were associated with better prognosis for COVID-19. Therefore, pragmatic trials to assess the potential therapeutic benefits of renin-angiotensin-aldosterone system inhibitors should be urgently promoted by health authorities to widen the therapeutic options for COVID-19.

Reduction of ACE2 Serum Concentrations by Telbivudine in Chronic Hepatitis B Patients.

BACKGROUND: Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has wreaked havoc worldwide since December 2019. Currently, no effective medical treatments have been approved. As the epidemic continues to spread, SARS-CoV-2 mutants emerge, some of which become more infectious with increasing vaccine resistance. The main route for SARS-CoV-2 to enter the host cells is by binding its spike protein to the host receptor, angiotensin-converting enzyme 2 (ACE2). Besides the membrane-bound form of ACE2, the soluble form of ACE2 (sACE2) can also bind SARS-CoV-2 for viral endocytosis. OBJECTIVE: Previously, we found that telbivudine reduced the concentrations of ACE1 in blood. Therefore, we speculated that this drug might also reduce the concentrations of sACE2. METHODS: In this retrospective study, serum samples from 39 hepatitis B patients receiving telbivudine were collected and examined for sACE2 concentrations using an ELISA kit.. RESULTS: It was found that the serum concentrations of sACE2 were significantly declined in chronic hepatitis B patients treated with telbivudine. CONCLUSION: Telbivudine treatment reduced sACE2 concentrations, which could potentially reduce the infection risk of SARS-CoV-2.

Angiotensin-converting enzyme 2 in human plasma and lung tissue.

PURPOSE: We investigated plasma angiotensin-converting enzyme 2 (ACE2) concentration in a population sample and the ACE2 expression quantitated with the diaminobenzidine mean intensity in the lung tissue in patients who underwent lung surgery. MATERIALS AND METHODS: The study participants were recruited from a residential area in the suburb of Shanghai for the plasma ACE2 concentration study (n = 503) and the lung tissue samples were randomly selected from the storage in Ruijin Hospital (80 men and 78 age-matched women). RESULTS: In analyses adjusted for covariables, men had a significantly higher plasma ACE2 concentration (1.21 vs. 0.98 ng/mL, p = 0.027) and the mean intensity of ACE2 in the lung tissue (55.1 vs. 53.9 a.u., p = 0.037) than women. With age increasing, plasma ACE2 concentration decreased (p = 0.001), while the mean intensity of ACE2 in the lung tissue tended to increase (p = 0.087). Plasma ACE2 concentration was higher in hypertension than normotension, especially treated hypertension (1.23 vs. 0.98 ng/mL, p = 0.029 vs. normotension), with no significant difference between users of RAS inhibitors and other classes of antihypertensive drugs (p = 0.64). There was no significance of the mean intensity of ACE2 in the lung tissue between patients taking and those not taking RAS inhibitors (p = 0.14). Neither plasma ACE2 concentration nor the mean intensity of ACE2 in the lung tissue differed between normoglycemia and diabetes (p ≥ 0.20). CONCLUSION: ACE2 in the plasma and lung tissue showed divergent changes according to several major characteristics of patients.Plain language summary What is the context? • The primary physiological function of ACE2 is the degradation of angiotensin I and II to angiotensin 1-9 and 1-7, respectively. • ACE2 was found to behave as a mediator of the severe acute respiratory syndrome coronavirus (SARS) infection. • There is little research on ACE2 in humans, especially in the lung tissue. • In the present report, we investigated plasma ACE2 concentration and the ACE2 expression quantitated with the diaminobenzidine mean intensity in the lung tissue respectively in two study populations. What is new? • Our study investigated both circulating and tissue ACE2 in human subjects. The main findings were: • In men as well as women, plasma ACE2 concentration was higher in younger than older participants, whereas the mean intensity of ACE2 in the lung tissue increase with age increasing. • Compared with normotension, hypertensive patients had higher plasma ACE2 concentration but similar mean intensity of ACE2 in the lung tissue. • Neither plasma ACE2 concentration nor lung tissue ACE2 expression significantly differed between users of RAS inhibitors and other classes of antihypertensive drugs. What is the impact? • ACE2 in the plasma and lung tissue showed divergent changes according to several major characteristics, such as sex, age, and treated and untreated hypertension. • A major implication is that plasma ACE2 concentration might not be an appropriate surrogate for the ACE2 expression in the lung tissue, and hence not a good predictor of SARS-COV-2 infection or fatality.

Positive Effect of a Pea-Clam Two-Peptide Composite on Hypertension and Organ Protection in Spontaneously Hypertensive Rats.

In the present study, we prepared pea peptides with high angiotensin-converting enzyme (ACE) inhibitory activity in vitro using an enzymatic hydrolysis of pea protein and compounded them with clam peptides to obtain a pea-clam double peptide. The effects of the two-peptide composite and pea peptides on hypertension and the damage-repair of corresponding organs were studied in spontaneously hypertensive rats (SHRs). We found that both pea peptides and the two-peptide composite significantly reduced the blood pressure upon a single or long-term intragastric administration, with the two-peptide composite being more effective. Mechanistically, we found that the two-peptide composite could regulate the renal renin-angiotensin system (RAS), rebalance gut microbial dysbiosis, decrease renal and myocardial fibrosis, and improve renal and cardiac function and vascular remodeling. Additionally, hippocampal lesions caused by hypertension were also eliminated after two-peptide composite administration. Our research provides a scientific basis for the use of this two-peptide composite as a safe antihypertension ingredient in functional foods.

Effect of Casein Hydrolysate on Cardiovascular Risk Factors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Casein hydrolysate has various biological functional activities, especially prominent are angiotensin I-converting enzyme inhibitory activities. Increasing evidence has reported the prominent hypotensive effect of casein hydrolysate. However, the effects of casein hydrolysate on cardiovascular risk factors remain unclear and require more comprehensive and detailed studies. Here, we conducted a systematic review and meta-analysis on eligible randomized controlled trials (RCTs) to summarize the effects of casein hydrolysate supplementation on blood pressure, blood lipids, and blood glucose. In the pooled analyses, casein hydrolysate significantly reduced systolic blood pressure by 3.20 mmHg (-4.53 to -1.87 mmHg) and diastolic blood pressure by 1.50 mmHg (-2.31 to -0.69 mmHg). Supplementation of casein hydrolysate displayed no effect on total cholesterol (-0.07 mmol/L; -0.17 to 0.03 mmol/L), low-density lipoprotein cholesterol (-0.04 mmol/L; -0.15 to 0.08 mmol/L), high-density lipoprotein cholesterol (-0.01 mmol/L; -0.06 to 0.03 mmol/L), triglycerides (-0.05 mmol/L, -0.14 to 0.05 mmol/L), or fasting blood glucose (-0.01 mmol/L; -0.10 to 0.09 mmol/L) compared with the placebo diets. Collectively, this study indicated that supplementation of casein hydrolysate displayed decreasing effect on blood pressure without affecting blood lipids or glycemic status.

Tissue- and cell-expression of druggable host proteins provide insights into repurposing drugs for COVID-19.

Several human host proteins play important roles in the lifecycle of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many drugs targeting these host proteins have been investigated as potential therapeutics for coronavirus disease 2019 (COVID-19). The tissue-specific expressions of selected host proteins were summarized using proteomics data retrieved from the Human Protein Atlas, ProteomicsDB, Human Proteome Map databases, and a clinical COVID-19 study. Protein expression features in different cell lines were summarized based on recent proteomics studies. The half-maximal effective concentration or half-maximal inhibitory concentration values were collected from in vitro studies. The pharmacokinetic data were mainly from studies in healthy subjects or non-COVID-19 patients. Considerable tissue-specific expression patterns were observed for several host proteins. ACE2 expression in the lungs was significantly lower than in many other tissues (e.g., the kidneys and intestines); TMPRSS2 expression in the lungs was significantly lower than in other tissues (e.g., the prostate and intestines). The expression levels of endocytosis-associated proteins CTSL, CLTC, NPC1, and PIKfyve in the lungs were comparable to or higher than most other tissues. TMPRSS2 expression was markedly different between cell lines, which could be associated with the cell-dependent antiviral activities of several drugs. Drug delivery receptor ICAM1 and CTSB were expressed at a higher level in the lungs than in other tissues. In conclusion, the cell- and tissue-specific proteomics data could help interpret the in vitro antiviral activities of host-directed drugs in various cells and aid the transition of the in vitro findings to clinical research to develop safe and effective therapeutics for COVID-19.

Selection of Bis-Indolyl Pyridines and Triphenylamines as New Inhibitors of SARS-CoV-2 Cellular Entry by Modulating the Spike Protein/ACE2 Interfaces.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the infectious agent that has caused the current coronavirus disease (COVID) pandemic. Viral infection relies on the viral S (spike) protein/cellular receptor ACE2 interaction. Disrupting this interaction would lead to early blockage of viral replication. To identify chemical tools to further study these functional interfaces, 139,146 compounds from different chemical libraries were screened through an S/ACE2 in silico virtual molecular model. The best compounds were selected for further characterization using both cellular and biochemical approaches, reiterating SARS-CoV-2 entry and the S/ACE2 interaction. We report here two selected hits, bis-indolyl pyridine AB-00011778 and triphenylamine AB-00047476. Both of these compounds can block the infectivity of lentiviral vectors pseudotyped with the SARS-CoV-2 S protein as well as wild-type and circulating variant SARS-CoV-2 strains in various human cell lines, including pulmonary cells naturally susceptible to infection. AlphaLISA and biolayer interferometry confirmed a direct inhibitory effect of these drugs on the S/ACE2 association. A specific study of the AB-00011778 inhibitory properties showed that this drug inhibits viral replication with a 50% effective concentration (EC50) between 0.1 and 0.5 µM depending on the cell lines. Molecular docking calculations of the interaction parameters of the molecules within the S/ACE2 complex from both wild-type and circulating variants of the virus showed that the molecules may target multiple sites within the S/ACE2 interface. Our work indicates that AB-00011778 constitutes a good tool for modulating this interface and a strong lead compound for further therapeutic purposes.

Connecting the dots between inflammatory cascades of obesity and COVID-19 in light of mortal consequences-a review.

Obesity is a term that has recently been referred to describe a condition in which a person has become a diseased vessel. Obesity's internal pathology is too mysterious as it has a close resemblance with fatal diseases pathology. Obesity and coronavirus disease 2019 (COVID-19) are simultaneous epidemics declared by many organizations after observing their rampage in the recent world. Oxidative stress, cytokine storm, interleukin, and their contribution to the internal adipocyte environment implicated in the cascades of inflammatory pathology are portrayed here. Major determinants like angiotensin-converting enzyme 2 (ACE2) and renin-angiotensin-aldosterone system (RAAS) axis are highly sensitive molecular factors. Data from various countries suggested a clinical overview of how greater body mass index (BMI) is related to greater COVID-19 risk. It also gives insight into how obese individuals are obligately getting admitted and combating COVID-19 in intensive care unit including children less than 13 years of age under ultimate therapeutic options. There are numerous studies currently taking place for finding a cure for obesity which are mainly focused on natural resources and novel therapies like photobiomodulation (PBM) consisting of laser treatment, infrared treatment, etc. as current pharmacological treatments are reported to have fatal adverse effects. Finally, it is discussed how attenuating obesity will be a solution for future combat strategy. This review gives light on the areas of coagulation, inflammatory parameters, cardiometabolic complications, endothelial dysfunctions, immunological infirmity due to COVID-19 in obese individuals. A conceptual outline about correlation between the inflammatory pathophysiological steps triggering the aggravation of fatal consequences has been drawn in this review.

[Role of ACE2 in COVID-19].

In the renin-angiotensin system (RAS), angiotensin II (AngII) converted by angiotensin converting enzyme (ACE) exerts a strong physiological activity via the AT1 receptor (AT1R). Thus, the ACE-AngII-AT1R axis positively regulates RAS. On the other hand, angiotensin converting enzyme 2 (ACE2) is known to negatively regulate RAS by degrading AngII into angiotensin 1-7 (Ang1-7). In the acute respiratory distress syndrome (ARDS), which is characterized by pulmonary hyperinflammation, the AngII-AT1R axis acts to exacerbate ARDS and the ACE2-AT2R axis acts protectively. More recently, ACE2 has been shown to be a receptor for SARS-CoV, the causative virus of severe acute respiratory syndrome (SARS), and SARS-CoV2, the causative virus of the 2019 coronavirus infection (COVID-19). Therefore, inhibition of the binding between ACE2 and virus spike protein is a drug discovery target for antiviral drugs against SARS-CoV and SARS-CoV2. In addition, when SARS and COVID-19 become severe, ARDS with cytokine storm is occured. We reported that soluble ACE2 protein and microbial-derived ACE2 like enzyme suppress pulmonary hyperinflammation due to SARS and COVID-19, respectively. In addition, it has been reported that the ACE2-soluble protein has an effect of suppressing the establishment of infection by inhibiting the binding between SARS-CoV2 and the cell membrane surface ACE2. Here, we describe the role of ACE2 in the pathophysiology of SARS/COVID-19 from the perspectives of inhibiting the progression to ARDS by suppressing pulmonary inflammation and suppressing the replication of the virus by inhibiting the binding of ACE2 to the spike protein.

Quercetin Reduces the Virulence of S. aureus by Targeting ClpP to Protect Mice from MRSA-Induced Lethal Pneumonia.

The dramatic increase of methicillin-resistant Staphylococcus aureus (MRSA) poses a great challenge to the treatment of Staphylococcus aureus (S. aureus) infections. Therefore, there is an urgent need to identify novel anti-infective agents to attack new targets to overcome antibiotic resistance. Casein hydrolase P (ClpP) is a key virulence factor in S. aureus to maintain cellular homeostasis. We screened from flavonoids and finally determined that quercetin could effectively attenuate the virulence of MRSA. The results of the thermal shift assay showed that quercetin could bind to ClpP and reduce the thermal stability of ClpP, and the KD value between quercetin and ClpP was 197 nM as determined by localized surface plasmon resonance. We found that quercetin exhibited a protective role of a mouse model of MRSA-induced lethal infection in a murine model. Based on the above facts, quercetin, as a ClpP inhibitor, could be further developed as a potential candidate for antivirulence agents to combat S. aureus infections. IMPORTANCE The resistance of Staphylococcus aureus (S. aureus) to various antibiotics has increased dramatically, and thus the development of new anti-infective drugs with new targets is urgently needed to combat resistance. Caseinolytic peptidase P (ClpP) is a casein hydrolase that has been shown to regulate a variety of important virulence factors in S. aureus. Here, we found that quercetin, a small-molecule compound from traditional Chinese herbal flavonoids, effectively inhibits ClpP activity. Quercetin attenuates the expression of multiple virulence factors in S. aureus and effectively protects mice from lethal pneumonia caused by MRSA. In conclusion, we determined that quercetin is a ClpP inhibitor and an effective lead compound for the development of a virulence factor-based treatment for S. aureus infection.

Mechanical dependency of the SARS-CoV-2 virus and the renin-angiotensin-aldosterone (RAAS) axis: a possible new threat.

Pathogens in our environment can act as agents capable of inflicting severe human diseases. Among them, the SARS-CoV-2 virus has recently plagued the globe and paralyzed the functioning of ordinary human life. The virus enters the cell through the angiotensin-converting enzyme-2 (ACE-2) receptor, an integral part of the renin-angiotensin system (RAAS). Reports on hypertension and its relation to the modulation of the RAAS are generating interest in the scientific community. This short review focuses on the SARS-CoV-2 infection's direct and indirect effects on our body through modulation of the RAAS axis. A patient having severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, which causes COVID-19 relates to hypertension as a pre-existing disease or develops it in a post-COVID scenario. Several studies on how SARS-CoV-2 modulates the RAAS axis indicate that it alters our body's physiological balance. This review seeks to establish a hypothesis on the mechanical dependency of SARS-CoV-2 and RAAS modulation in the human body. This study intends to impart ideas on drug development and designing by targeting the modulation of the RAAS axis to inactivate the pathogenicity of the SARS-CoV-2 virus. A systematic hypothesis can severely attenuate the pathogenicity of the dreadful viruses of the future.

Involvement of the Renin-Angiotensin System in Stress: State of the Art and Research Perspectives.

BACKGROUND: Along with other canonical systems, the renin-angiotensin system (RAS) has shown important roles in stress. This system is a complex regulatory proteolytic cascade composed of various enzymes, peptides, and receptors. Besides the classical (ACE/Ang II/AT1 receptor) and the counter-regulatory (ACE2/Ang-(1-7)/Mas receptor) RAS axes, evidence indicates that nonclassical components, including Ang III, Ang IV, AT2 and AT4, can also be involved in stress. OBJECTIVE AND METHODS: This comprehensive review summarizes the current knowledge on the participation of RAS components in different adverse environmental stimuli stressors, including air jet stress, cage switch stress, restraint stress, chronic unpredictable stress, neonatal isolation stress, and post-traumatic stress disorder. RESULTS AND CONCLUSION: In general, activation of the classical RAS axis potentiates stress-related cardiovascular, endocrine, and behavioral responses, while the stimulation of the counter-regulatory axis attenuates these effects. Pharmacological modulation in both axes is optimistic, offering promising perspectives for stress-related disorders treatment. In this regard, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are potential candidates already available since they block the classical axis, activate the counter-regulatory axis, and are safe and efficient drugs.

Angiotensin I-converting enzyme inhibitory peptide: an emerging candidate for vascular dysfunction therapy.

Abnormal vasoconstriction, inflammation, and vascular remodeling can be promoted by angiotensin II (Ang II) in the renin-angiotensin system (RAS), leading to vascular dysfunction diseases such as hypertension and atherosclerosis. Researchers have recently focused on angiotensin I-converting enzyme inhibitory peptides (ACEIPs), that have desirable efficacy in vascular dysfunction therapy due to Ang II reduction by inhibiting ACE activity. Promising methods for the large-scale preparation of ACEIPs include selective enzymatic hydrolysis and microbial fermentation. Thus far, ACEIPs have been widely reported to be hydrolyzed from protein-rich sources, including animals, plants, and marine organisms, while many emerging microorganism-derived ACEIPs are theoretically biosynthesized through the nonribosomal peptide synthase (NRPS) pathway. Notably, vasodilatation, anti-inflammation, and vascular reconstruction reversal of ACEIPs are strongly correlated. However, the related molecular mechanisms underlying signal transduction regulation in vivo remain unclear. We provide a comprehensive update of the ACE-Ang II-G protein-coupled type 1 angiotensin receptor (AT1R) axis signaling and its functional significance for potential translation into therapeutic strategies, particularly targeting AT1R by ACEIPs, as well as specific related signaling pathways. Future studies are expected to verify the biosynthetic regulatory mechanism of ACEIPs via the NRPS pathway, the effect of gut microbiota metabolism on vascular dysfunction and rigorous studies of ACE-Ang II-AT1R signaling pathways mediated by ACEIPs in large animals and humans.

Soluble ACE2 Is Filtered into the Urine.

Background: ACE2 is a key enzyme in the renin-angiotensin system (RAS) capable of balancing the RAS by metabolizing angiotensin II (AngII). First described in cardiac tissue, abundance of ACE2 is highest in the kidney, and it is also expressed in several extrarenal tissues. Previously, we reported an association between enhanced susceptibility to hypertension and elevated renal AngII levels in global ACE2-knockout mice. Methods: To examine the effect of ACE2 expressed in the kidney, relative to extrarenal expression, on the development of hypertension, we used a kidney crosstransplantation strategy with ACE2-KO and WT mice. In this model, both native kidneys are removed and renal function is provided entirely by the transplanted kidney, such that four experimental groups with restricted ACE2 expression are generated: WT→WT (WT), KO→WT (KidneyKO), WT→KO (SystemicKO), and KO→KO (TotalKO). Additionally, we used nanoscale mass spectrometry-based proteomics to identify ACE2 fragments in early glomerular filtrate of mice. Results: Although significant differences in BP were not detected, a major finding of our study is that shed or soluble ACE2 (sACE2) was present in urine of KidneyKO mice that lack renal ACE2 expression. Detection of sACE2 in the urine of KidneyKO mice during AngII-mediated hypertension suggests that sACE2 originating from extrarenal tissues can reach the kidney and be excreted in urine. To confirm glomerular filtration of ACE2, we used micropuncture and nanoscale proteomics to detect peptides derived from ACE2 in the Bowman's space. Conclusions: Our findings suggest that both systemic and renal tissues may contribute to sACE2 in urine, identifying the kidney as a major site for ACE2 actions. Moreover, filtration of sACE2 into the lumen of the nephron may contribute to the pathophysiology of kidney diseases characterized by disruption of the glomerular filtration barrier.

Evidence for Use or Disuse of Renin-Angiotensin System Modulators in Patients Having COVID-19 With an Underlying Cardiorenal Disorder.

Coronavirus disease 19 (COVID-19) originated in Wuhan, China, in December 2019 has been declared pandemic by World Health Organization due to an exponential rise in the number of infected and deceased persons across the globe. Emerging reports suggest that susceptibility and mortality rates are higher in patients with certain comorbidities when compared to the average population. Cardiovascular diseases and diabetes are important risk factors for a lethal outcome of COVID-19. Extensive research ensuing the outbreak of coronavirus-related severe acute respiratory syndrome in the year 2003, and COVID-19 recently revealed a role of renin-angiotensin system (RAS) components in the entry of coronavirus wherein angiotensin-converting enzyme 2 (ACE2) had garnered the significant attention. This raises the question whether the use of RAS inhibitors, the backbone of treatment of cardiovascular, neurovascular, and kidney diseases could increase the susceptibility for coronavirus infection or unfortunate outcomes of COVID-19. Thus, currently, there is a lack of consensus regarding the effects of RAS inhibitors in such patients. Moreover, expert bodies like American Heart Association, American College of Cardiology, and so on have now released official statements that RAS inhibitors must be continued, unless suggested otherwise by a physician. In this brief review, we will elaborate on the role of RAS and ACE2 in pathogenesis of COVID-19. Moreover, we will discuss the potential effect of the use and disuse of RAS inhibitors in patients having COVID-19 with cardiometabolic comorbidities.