ACE2 activator diminazene aceturate exerts renoprotective effects in gentamicin-induced acute renal injury in rats

Abstract Acute Kidney Injury (AKI) comprises a rapidly developed renal failure and is associated with high mortality rates. The Renin–Angiotensin System (RAS) plays a pivotal role in AKI, as the over-active RAS axis exerts major deleterious effects in disease progression. In this sense, the conversion of Angiotensin II (Ang II) into Angiotensin-(1-7) (Ang-(1-7)) by the Angiotensin-converting enzyme 2 (ACE2) is of utmost importance to prevent worse clinical outcomes. Previous studies reported the beneficial effects of oral diminazene aceturate (DIZE) administration, an ACE2 activator, in renal diseases models. In the present study, we aimed to evaluate the therapeutic effects of DIZE administration in experimental AKI induced by gentamicin (GM) in rats. Our findings showed that treatment with DIZE improved renal function and tissue damage by increasing Ang-(1-7) and ACE2 activity, and reducing TNF-α. These results corroborate with a raising potential of ACE2 activation as a strategy for treating AKI.

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Anti-Inflammatory Properties of Drugs Used to Control COVID-19 and their Effects on the Renin-Angiotensin System and Angiotensin-Converting Enzyme-2

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/jpps31346 ◽

2020 ◽

Vol 23 ◽

pp. 259-277

Author(s):

Hamed Gilzad-Kohan ◽

Fakhreddin Jamali

Keyword(s):

Survival Rates ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Beneficial Effects ◽

Reactive Protein ◽

Crucial Component ◽

Tnf Α ◽

Anti Inflammatory ◽

Severity Of The Disease

Covid-19 infection is associated with systemic inflammation, as do other infections. COVID-19 in some patients is associated with hyperinflammatory responses, which might lead to a cytokine storm. This phenomenon plays a major role in COVID-19 severity and death, and usually associated with poor disease prognosis. Higher levels of inflammatory hallmarks including C-reactive protein, ferritin, D-dimers, and cytokines such as L-6, IL-10, and TNF-α has been observed in severe cases of the disease. Many anti-viral drugs have been tried to eradicate the virus, none were proven fully effective. Supportive care and management of the complications that are caused mainly by inflammation might be the key element for greater survival rates and shorter periods of mechanical ventilation and overall hospitalization. However, the efficacy of these treatments still needs well-planned clinical trials. In such trials, careful attention must be paid to the duration of the treatment, the onset of beneficial effects, and the severity of the disease, otherwise, the outcomes may still remain inconclusive. Herein, we present a review of the current drugs, which are being used in the management of the disease and their anti-inflammatory properties. We also investigated if these drugs directly interact with ACE 2, which is a crucial component of the virus entry to the cells.

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ACE2 Shedding and the Role in COVID-19

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.789180 ◽

2022 ◽

Vol 11 ◽

Author(s):

Jieqiong Wang ◽

Huiying Zhao ◽

Youzhong An

Keyword(s):

Amino Acids ◽

Viral Entry ◽

Kidney Injury ◽

Renin Angiotensin System ◽

Underlying Mechanism ◽

Ang Ii ◽

Converting Enzyme ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Transmembrane Glycoprotein

Angiotensin converting enzyme 2 (ACE2), a transmembrane glycoprotein, is an important part of the renin-angiotensin system (RAS). In the COVID-19 epidemic, it was found to be the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). ACE2 maintains homeostasis by inhibiting the Ang II-AT1R axis and activating the Ang I (1-7)-MasR axis, protecting against lung, heart and kidney injury. In addition, ACE2 helps transport amino acids across the membrane. ACE2 sheds from the membrane, producing soluble ACE2 (sACE2). Previous studies have pointed out that sACE2 plays a role in the pathology of the disease, but the underlying mechanism is not yet clear. Recent studies have confirmed that sACE2 can also act as the receptor of SARS-COV-2, mediating viral entry into the cell and then spreading to the infective area. Elevated concentrations of sACE2 are more related to disease. Recombinant human ACE2, an exogenous soluble ACE2, can be used to supplement endogenous ACE2. It may represent a potent COVID-19 treatment in the future. However, the specific administration concentration needs to be further investigated.

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Mechanism of ligand recognition by human ACE2 receptor

10.1101/2020.10.30.362749 ◽

2020 ◽

Author(s):

Apurba Bhattarai ◽

Shristi Pawnikar ◽

Yinglong Miao

Keyword(s):

Ligand Binding ◽

Renin Angiotensin System ◽

Rational Drug Design ◽

Renal Diseases ◽

Ligand Recognition ◽

Conformational Ensemble ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Accelerated Molecular Dynamics ◽

Rational Drug

AbstractAngiotensin converting enzyme 2 (ACE2) plays a key role in renin-angiotensin system regulation and amino acid homeostasis. Human ACE2 acts as the receptor for severe acute respiratory syndrome coronaviruses SARS-CoV and SARS-CoV-2. ACE2 is also widely expressed in epithelial cells of lungs, heart, kidney and pancreas. It is considered an important drug target for treating SARS-CoV-2, as well as pulmonary diseases, heart failure, hypertension, renal diseases and diabetes. Despite the critical importance, the mechanism of ligand binding to the human ACE2 receptor remains unknown. Here, we address this challenge through all-atom simulations using a novel ligand Gaussian accelerated molecular dynamics (LiGaMD) method. Microsecond LiGaMD simulations have successfully captured both binding and unbinding of the MLN-4760 inhibitor in the ACE2 receptor. In the ligand unbound state, the ACE2 receptor samples distinct Open, Partially Open and Closed conformations. Ligand binding biases the receptor conformational ensemble towards the Closed state. The LiGaMD simulations thus suggest a conformational selection mechanism for ligand recognition by the ACE2 receptor. Our simulation findings are expected to facilitate rational drug design of ACE2 against coronaviruses and other related human diseases.

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Reduced urinary levels of angiotensin-converting enzyme 2 activity predict acute kidney injury in critically ill patients

Critical Care and Resuscitation ◽

10.51893/2020.4.oa7 ◽

2020 ◽

Vol 22 (4) ◽

pp. 344-354

Author(s):

Laurent Bitker ◽

◽

Sheila K Patel ◽

Intissar Bittar ◽

Glenn M Eastwood ◽

...

Keyword(s):

Intensive Care Unit ◽

Acute Kidney Injury ◽

Angiotensin Converting Enzyme ◽

Kidney Injury ◽

Renin Angiotensin System ◽

Urine Collection ◽

Converting Enzyme ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Urine Creatinine

Objective: Angiotensin-converting enzyme 2 activity reflects non-classical renin–angiotensin system upregulation. We assessed the association of urinary angiotensin-converting enzyme 2 (uACE2) activity with acute kidney injury (AKI). Design, setting and participants: A prospective observational study in which we measured uACE2 activity in 105 critically ill patients at risk of AKI. We report AKI stage 2 or 3 at 12 hours of urine collection (AKI12h) and AKI stage 2 or 3 at any time during intensive care unit stay in patients free from any stage of AKI at inclusion (AKIICU). AKI prediction was assessed using area under the receiver-operating characteristics curve (AUROC) and net reclassification indices (NRIs). Main outcome measure: AKI stage 2 or 3 at 12 hours of urine collection. Results: Within 12 hours of inclusion, 32 of 105 patients (30%) had developed AKI12h. Corrected uACE2 activity was significantly higher in patients without AKI12h compared with those with AKI12h (median [interquartile range], 13 [6–24] v 7 [4–10] pmol/min/mL per mmol/L of urine creatinine; P < 0.01). A 10-unit increase in uACE2 was associated with a 28% decrease in AKI12h risk (odds ratio [95% CI], 0.72 [0.46–0.97]). During intensive care unit admission, 39 of 76 patients (51%) developed AKIICU. uACE2 had an AUROC for the prediction of AKI12h of 0.68 (95% CI, 0.57–0.79), and correctly reclassified 28% of patients (positive NRI) to AKI12h. Patients with uACE2 > 8.7 pmol/min/mL per mmol/L of urine creatinine had a significantly lower risk of AKIICU on log-rank analysis (52% v 84%; P < 0.01). Conclusions: Higher uACE2 activity was associated with a decreased risk of AKI stage 2 or 3. Our findings support future evaluations of the role of the non-classical renin–angiotensin system during AKI.

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COVID-19 and Renal Diseases: An Update

Current Drug Targets ◽

10.2174/1389450121999201013151300 ◽

2020 ◽

Vol 22 (1) ◽

pp. 52-67

Author(s):

Letícia Bitencourt Cota ◽

Ana Luisa Pedrosa ◽

Stephanie Bruna Camilo Soares de Brito ◽

Ana Cláudia Fontoura Fróes ◽

Sarah Tayná de Carvalho ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Acute Kidney Injury ◽

Kidney Disease ◽

Kidney Injury ◽

Renin Angiotensin System ◽

Renal Diseases ◽

Angiotensin Converting Enzyme 2 ◽

Immunosuppressive Medications ◽

Immune Alterations ◽

Current Scenario

Background: It becomes increasingly evident that the SARS-CoV-2 infection is not limited to the respiratory system. In addition to being a target of the virus, the kidney also seems to have substantial influence on the outcomes of the disease. Methods: Data was obtained by a comprehensive and non-systematic search in the PubMed, Cochrane, Scopus and SciELO databases, using mainly the terms “SARS-CoV-2”, “COVID-19”, “chronic kidney disease”, “renal transplantation”, acute kidney injury” and “renal dysfunction”. Discussion: The membrane-bound angiotensin converting enzyme 2 is the receptor for SARS-CoV-2, and this interaction may lead to an imbalance of the Renin Angiotensin System (RAS), associated with worse clinical presentations of COVID-19, including acute pulmonary injury, hyperinflammatory state and hematological alterations. In the framework of renal diseases, development of acute kidney injury is associated mostly with immune alterations and direct cytopathic lesions by the virus, leading to higher mortality. As for chronic kidney disease, the patients at a non-terminal stage have worse prog-nosis, while the hemodialysis patients appear to have mild courses of COVID-19, probably due to lower chances of being affected by the cytokine storm. Furthermore, the current scenario is unfavorable to kidney donation and transplantation. The relationship between COVID-19 and immunosuppression in kidney transplantation recipients has been greatly discussed to determine whether it increases mortality and how it interacts with immunosuppressive medications. Conclusion: The kidney and the RAS exert fundamental roles in the SARS-CoV-2 infection and more research is required to have a complete understanding on the repercussions caused by COVID-19 in renal diseases.

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Activation of renal renin-angiotensin system in upstream stimulatory factor 2 transgenic mice

AJP Renal Physiology ◽

10.1152/ajprenal.90493.2008 ◽

2009 ◽

Vol 296 (2) ◽

pp. F257-F265 ◽

Cited By ~ 13

Author(s):

Lihua Shi ◽

Dejan Nikolic ◽

Shu Liu ◽

Hong Lu ◽

Shuxia Wang

Keyword(s):

Transforming Growth Factor ◽

Mesangial Cells ◽

Kidney Injury ◽

Renin Angiotensin System ◽

Renal Diseases ◽

Ang Ii ◽

Upstream Stimulatory Factor ◽

Angiotensin System ◽

Renin Angiotensin ◽

Stimulatory Factor

Previously we demonstrated that upstream stimulatory factor 2 (USF2) transgenic (Tg) mice developed nephropathy including albuminuria and glomerular hypertrophy, accompanied by increased transforming growth factor (TGF)-β and fibronectin accumulation in the glomeruli. However, the mechanisms by which overexpression of USF2 induces kidney injury are unknown. USF has been shown to regulate renin expression. Moreover, the renin-angiotensin system (RAS) plays important roles in renal diseases. Therefore, in the present studies the effects of USF2 on the regulation of RAS in the kidney as well as in mesangial cells from USF2 (Tg) mice were examined. The role of USF2-mediated regulation of RAS in TGF-β production in mesangial cells was also determined. Our data demonstrate that USF2 (Tg) mice exhibit increased renin and angiotensin (ANG) II levels in the kidney. In contrast, renal expression of other components of RAS such as renin receptor, angiotensinogen, angiotensin-converting enzyme (ACE), ACE2, angiotensin type 1a (AT1a) receptor, and AT2 receptor was not altered in USF2 (Tg) mice. Similarly, mesangial cells isolated from USF2 (Tg) mice had increased renin and ANG II levels. Mesangial cells overexpressing USF2 also had increased TGF-β production, which was blocked by small interfering RNA-mediated renin gene knockdown or RAS blockade (enalapril or losartan). Collectively, these results suggest that USF2 promotes renal renin expression and stimulates ANG II generation, leading to activation of the intrarenal RAS. In addition, renin-dependent ANG II generation mediates the effect of USF2 on TGF-β production in mesangial cells, which may contribute to the development of nephropathy in USF2 (Tg) mice.

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Androgens, the kidney, and COVID-19: an opportunity for translational research

AJP Renal Physiology ◽

10.1152/ajprenal.00601.2020 ◽

2021 ◽

Vol 320 (2) ◽

pp. F243-F248

Author(s):

Licy L. Yanes Cardozo ◽

Samar Rezq ◽

Jacob E. Pruett ◽

Damian G. Romero

Keyword(s):

Kidney Diseases ◽

Kidney Injury ◽

Renin Angiotensin System ◽

Renal Diseases ◽

Angiotensin System ◽

Chronic Kidney Diseases ◽

Sex Disparities ◽

Male Patients ◽

Male Sex

Coronavirus disease 2019 (COVID-19) has reached pandemic proportions, affecting millions of people worldwide. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of COVID-19. Epidemiological reports have shown that the severity of SARS-CoV-2 infection is associated with preexisting comorbidities such as hypertension, diabetes mellitus, cardiovascular diseases, and chronic kidney diseases, all of which are also risk factors for acute kidney injury (AKI). The kidney has emerged as a key organ affected by SARS-CoV-2. AKI is associated with increased morbidity and mortality in patients with COVID-19. Male sex is an independent predictor for AKI, and an increased death rate has been reported in male patients with COVID-19 worldwide. The mechanism(s) that mediate the sex discrepancy in mortality due to COVID-19 remain(s) unknown. Angiotensin-converting enzyme (ACE)2 is the receptor for SARS-CoV-2. Alterations in the ACE-to-ACE2 ratio have been implicated in renal diseases. This perspective aims to discuss data that suggest that androgens, via alterations in the intrarenal renin-angiotensin system, impair renal hemodynamics, predisposing patients to AKI during COVID-19 infection, which could explain the higher mortality observed in men with COVID-19. Clinicians should ensure early and effective cardiometabolic control for all patients to ameliorate the compensatory elevation of ACE2 and alterations in the ACE-to-ACE2 ratio. A better understanding of the role of androgens in SARS-CoV-2-associated AKI and mortality is imperative. The kidney could constitute a key organ that may explain the sex disparities of the higher mortality and worst outcomes associated with COVID-19 in men.

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Angiotensin 1–7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity

AJP Renal Physiology ◽

10.1152/ajprenal.00655.2013 ◽

2014 ◽

Vol 306 (8) ◽

pp. F812-F821 ◽

Cited By ~ 62

Author(s):

Jun Mori ◽

Vaibhav B. Patel ◽

Tharmarajan Ramprasath ◽

Osama Abo Alrob ◽

Jessica DesAulniers ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetic Nephropathy ◽

Renin Angiotensin System ◽

Ang Ii ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Beneficial Effects ◽

Osmotic Pumps ◽

Characteristic Features ◽

Transcription 3

The renin-angiotensin system, especially angiotensin II (ANG II), plays a key role in the development and progression of diabetic nephropathy. ANG 1–7 has counteracting effects on ANG II and is known to exert beneficial effects on diabetic nephropathy. We studied the mechanism of ANG 1–7-induced beneficial effects on diabetic nephropathy in db/db mice. We administered ANG 1–7 (0.5 mg·kg−1·day−1) or saline to 5-mo-old db/db mice for 28 days via implanted micro-osmotic pumps. ANG 1–7 treatment reduced kidney weight and ameliorated mesangial expansion and increased urinary albumin excretion, characteristic features of diabetic nephropathy, in db/db mice. ANG 1–7 decreased renal fibrosis in db/db mice, which correlated with dephosphorylation of the signal transducer and activator of transcription 3 (STAT3) pathway. ANG 1–7 treatment also suppressed the production of reactive oxygen species via attenuation of NADPH oxidase activity and reduced inflammation in perirenal adipose tissue. Furthermore, ANG 1–7 treatment decreased lipid accumulation in db/db kidneys, accompanied by increased expressions of renal adipose triglyceride lipase (ATGL). Alterations in ATGL expression correlated with increased SIRT1 expression and deacetylation of FOXO1. The upregulation of angiotensin-converting enzyme 2 levels in diabetic nephropathy was normalized by ANG 1–7. ANG 1–7 treatment exerts renoprotective effects on diabetic nephropathy, associated with reduction of oxidative stress, inflammation, fibrosis, and lipotoxicity. ANG 1–7 can represent a promising therapy for diabetic nephropathy.

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ACE2 as therapeutic agent

Clinical Science ◽

10.1042/cs20200570 ◽

2020 ◽

Vol 134 (19) ◽

pp. 2581-2595

Author(s):

Qiuhong Li ◽

Maria B. Grant ◽

Elaine M. Richards ◽

Mohan K. Raizada

Keyword(s):

Therapeutic Agent ◽

Renin Angiotensin System ◽

Peptide Hormone ◽

Experimental Models ◽

Electrolyte Balance ◽

Ang Ii ◽

Angiotensin Converting Enzyme 2 ◽

Beneficial Effects ◽

Overwhelming Evidence ◽

Future Challenges

Abstract The angiotensin-converting enzyme 2 (ACE2) has emerged as a critical regulator of the renin–angiotensin system (RAS), which plays important roles in cardiovascular homeostasis by regulating vascular tone, fluid and electrolyte balance. ACE2 functions as a carboxymonopeptidase hydrolyzing the cleavage of a single C-terminal residue from Angiotensin-II (Ang-II), the key peptide hormone of RAS, to form Angiotensin-(1-7) (Ang-(1-7)), which binds to the G-protein–coupled Mas receptor and activates signaling pathways that counteract the pathways activated by Ang-II. ACE2 is expressed in a variety of tissues and overwhelming evidence substantiates the beneficial effects of enhancing ACE2/Ang-(1-7)/Mas axis under many pathological conditions in these tissues in experimental models. This review will provide a succinct overview on current strategies to enhance ACE2 as therapeutic agent, and discuss limitations and future challenges. ACE2 also has other functions, such as acting as a co-factor for amino acid transport and being exploited by the severe acute respiratory syndrome coronaviruses (SARS-CoVs) as cellular entry receptor, the implications of these functions in development of ACE2-based therapeutics will also be discussed.

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Outcomes of COVID-19 Hospitalized Patients Previously Treated with Renin-Angiotensin System Inhibitors

Journal of Clinical Medicine ◽

10.3390/jcm9113472 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3472 ◽

Cited By ~ 1

Author(s):

Elena-Mihaela Cordeanu ◽

Lucas Jambert ◽

Francois Severac ◽

Hélène Lambach ◽

Jonathan Tousch ◽

...

Keyword(s):

Renin Angiotensin System ◽

Severe Pneumonia ◽

University Hospital ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Previously Treated ◽

The Impact ◽

Harmful Effects ◽

Observation Period

(1) Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) penetrates respiratory epithelium through angiotensin-converting enzyme-2 binding, raising concerns about the potentially harmful effects of renin–angiotensin system inhibitors (RASi) on Human Coronavirus Disease 2019 (COVID-19) evolution. This study aimed to provide insight into the impact of RASi on SARS-CoV-2 outcomes in patients hospitalized for COVID-19. (2) Methods: This was a retrospective analysis of hospitalized adult patients with SARS-CoV-2 infection admitted to a university hospital in France. The observation period ended at hospital discharge. (3) Results: During the study period, 943 COVID-19 patients were admitted to our institution, of whom 772 were included in this analysis. Among them, 431 (55.8%) had previously known hypertension. The median age was 68 (56–79) years. Overall, 220 (28.5%) patients were placed under mechanical ventilation and 173 (22.4%) died. According to previous exposure to RASi, we defined two groups, namely, “RASi” (n = 282) and “RASi-free” (n = 490). Severe pneumonia (defined as leading to death and/or requiring intubation, high-flow nasal oxygen, noninvasive ventilation, and/or oxygen flow at a rate of ≥5 L/min) and death occurred more frequently in RASi-treated patients (64% versus 53% and 29% versus 19%, respectively). However, in a propensity score-matched cohort derived from the overall population, neither death (hazard ratio (HR) 0.93 (95% confidence interval (CI) 0.57–1.50), p = 0.76) nor severe pneumonia (HR 1.03 (95%CI 0.73–1.44), p = 0.85) were associated with RASi therapy. (4) Conclusion: Our study showed no correlation between previous RASi treatment and death or severe COVID-19 pneumonia after adjustment for confounders.

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