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Batlle D, Hassler L, Wysocki J. ACE2, From the Kidney to SARS-CoV-2: Donald Seldin Award Lecture 2023. Hypertension 2025; 82:166-180. [PMID: 39624896 DOI: 10.1161/hypertensionaha.124.22064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2025]
Abstract
ACE2 (angiotensin-converting enzyme 2) is a monocarboxypeptidase that cleaves Ang II (angiotensin II) among other substrates. ACE2 is present in the cell membrane of many organs, most abundantly in epithelial cells of kidney proximal tubules and the small intestine, and also exists in soluble forms in plasma and body fluids. Membrane-bound ACE2 exerts a renoprotective action by metabolizing Ang II and therefore attenuating the undesirable actions of excess Ang II. Therefore, soluble ACE2, by downregulating this peptide, may exert a therapeutic action. Our laboratory has designed ACE2 truncates that pass the glomerular filtration barrier to target the kidney renin-angiotensin system directly and, therefore, compensate for loss of kidney membrane-bound ACE2. Membrane-bound ACE2 is also the essential receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Soluble ACE2 proteins have been studied as a way to intercept SARS-CoV-2 from binding to membrane-bound ACE2 and prevent cell entry of SARS-CoV-2 altogether. We bioengineered a soluble ACE2 protein, termed ACE2 618-DDC-ABD, with increased binding affinity for SARS-CoV-2 and prolonged duration of action, which, when administered intranasally, provides near-complete protection from lethality in k18hACE2 mice infected with different SARS-CoV-2 variants. The main advantage of soluble ACE2 proteins for the neutralization of SARS-CoV-2 is their immediate onset of action and universality for current and future emerging SARS-CoV-2 variants. It is notable that ACE2 is critically involved in 2 dissimilar functions: as a receptor for cell entry of many coronaviruses and as an enzyme in the metabolism of Ang II, and yet in both cases, it is a therapeutic target.
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Affiliation(s)
- Daniel Batlle
- Division of Nephrology/Hypertension, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL
| | - Luise Hassler
- Division of Nephrology/Hypertension, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL
| | - Jan Wysocki
- Division of Nephrology/Hypertension, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL
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Li XQ, Xiao ZZ, Ma K, Liu XY, Liu HH, Hu B, Zhao Q, Li HY, Chen RC, Meng Y, Yin LH. Angiotensin-Converting Enzyme-Dependent Intrarenal Angiotensin II Contributes to CTP: Phosphoethanolamine Cytidylyltransferase Downregulation, Mitochondrial Membranous Disruption, and Reactive Oxygen Species Overgeneration in Diabetic Tubulopathy. Antioxid Redox Signal 2024. [PMID: 39495586 DOI: 10.1089/ars.2024.0637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2024]
Abstract
Aims: The limited therapeutic options for diabetic tubulopathy (DT) in early diabetic kidney disease (DKD) reflect the difficulty of targeting renal tubular compartment. While renin-angiotensin-aldosterone system (RAS) inhibitors are commonly utilized in the management of DKD, how intrarenal RAS contributes to diabetic tubular injury is not fully understood. Mitochondrial disruption and reactive oxygen species (ROS) overgeneration have been involved in diabetic tubular injury. Herein, we aim to test the hypothesis that angiotensin-converting enzyme (ACE)-dependent intrarenal angiotensin II (AngII) disrupts tubular mitochondrial membranous homeostasis and causes excessive ROS generation in DT. Results: Mice suffered from renal tubular mitochondrial disruption and ROS overgeneration following high-fat diet/streptozocin-type 2 diabetic induction. Intrarenal AngII generation is ACE-dependent in DT. Local AngII accumulation in renal tissues was achieved by intrarenal artery injection. ACE-dependent intrarenal AngII-treated mice exhibit markedly elevated levels of makers of tubular injury. CTP: Phosphoethanolamine cytidylyltransferase (PCYT2), the primary regulatory enzyme for the biosynthesis of phosphatidylethanolamine, was enriched in renal tubules according to single-cell RNA sequencing. ACE-dependent intrarenal AngII-induced tubular membranous disruption, ROS overgeneration, and PCYT2 downregulation. The diabetic ambiance deteriorated the detrimental effect of ACE-dependent intrarenal AngII on renal tubules. Captopril, the ACE inhibitor (ACEI), showed efficiency in partially ameliorating ACE-dependent intrarenal AngII-induced tubular deterioration pre- and post-diabetic induction. Innovation and Conclusion: This study uncovers a critical role of ACE-dependent intrarenal AngII in mitochondrial membranous disruption, ROS overgeneration, and PCYT2 deficiency in diabetic renal tubules, providing novel insight into DT pathogenesis and ACEI-combined therapeutic targets. Antioxid. Redox Signal. 00, 000-000.
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Affiliation(s)
- Xia-Qing Li
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
- Nephrology Department, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, China
| | - Zhang-Zhang Xiao
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
- Nephrology Department, Houjie Hospital of Dongguan, Dongguan, China
| | - Ke Ma
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
- Nephrology Department, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, China
| | - Xia-Yun Liu
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
- Nephrology Department, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, China
| | - Huan-Huan Liu
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Bo Hu
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Qian Zhao
- Department of Infectious Diseases and Hepatology Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hong-Yue Li
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
- Nephrology Department, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, China
| | - Rui-Chang Chen
- Department of Emergency Medicine, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Yu Meng
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
- Nephrology Department, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, China
- Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, China
| | - Liang-Hong Yin
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
- Huangpu Institute of Materials, Guangzhou, China
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Silva CNDF, Bessa ADSMD, Costa JMD, Lopes PR, Neves ÂR, Teles Bombardelli MML, Colugnati DB, Pedrino GR, Mendes EP, Santos RASD, Biancardi MF, Santos FCAD, Castro CH. Mas receptor blockade impairs exercise-induced cardiac hypertrophy. Peptides 2024; 181:171296. [PMID: 39265810 DOI: 10.1016/j.peptides.2024.171296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/06/2024] [Accepted: 09/09/2024] [Indexed: 09/14/2024]
Abstract
Exercise training leads to physiological cardiac hypertrophy and the protective axis of the renin-angiotensin system composed of angiotensin-converting enzyme 2, angiotensin-(1-7), and Mas receptor seems involved in this process. However, the role of the basal activity of the Mas receptor in exercise-induced physiological cardiac hypertrophy is still unclear. We evaluated the effects of the Mas receptor blockade on the left ventricular structure and function of rats submitted to running training. Rats were assigned to 4 groups: sedentary (S), sedentary + A-779 (Mas receptor antagonist, 120 µg/kg/day, i.p.; SA), trained (60-minute treadmill running sessions, five days a week, 8 weeks; T), and trained + A-779 (TA). Systolic blood pressure was higher in sedentary and trained rats treated with A-779 at the end of the experimental period. The A-779 treatment prevented the left ventricular hypertrophy evoked by physical exercise and increased collagen deposition in sedentary and trained rats. Cardiomyocytes from the SA group presented increased length and thickness of the sarcomeres, elongated mitochondria, glycogen deposits, and enlarged cisterns of the sarcoplasmic reticulum. TA group presented a reduced sarcomere thickness and cytoplasm with a degenerative aspect. These findings show that the basal activity of the Mas receptor is essential for the proper turnover of the extracellular matrix in the myocardium and the maintenance of the sarcomeric structure of cardiomyocytes.
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Affiliation(s)
| | | | | | - Paulo Ricardo Lopes
- Department of Physiological Sciences, Federal University of Goiás, Goiânia, GO, Brazil
| | - Ângela Ribeiro Neves
- Department of Physiological Sciences, Federal University of Goiás, Goiânia, GO, Brazil
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Hashemi ZS, Khalili S, Barough MS, Sarrami Forooshani R, Sanati H, Sarafrazi Esfandabadi F, Rasaee MJ, Nasirmoghadas P. Characterization of an engineered ACE2 protein for its improved biological features and its transduction into MSCs: A novel approach to combat COVID-19 infection. Int J Biol Macromol 2024; 277:134066. [PMID: 39059530 DOI: 10.1016/j.ijbiomac.2024.134066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 07/06/2024] [Accepted: 07/19/2024] [Indexed: 07/28/2024]
Abstract
Transduced MSCs that express engineered ACE2 could be highly beneficial to combat COVID-19. Engineered ACE2 can act as decoy targets for the virus, preventing its entry into healthy lung cells. To this end, genetic engineering techniques were used to integrate the ACE2 gene into the MSCs genome. The MSCs were evaluated for proper expression and functionality. The mutated form of ACE2 was characterized using various techniques such as protein expression analysis, binding affinity against spike protein, thermal stability assessment, and enzymatic activity assays. The functionality of the mACE2 was assessed on SARS-CoV-2 using the virus-neutralizing test. The obtained results indicated that by introducing specific mutations in the ACE2 gene, the resulting mutant ACE2 had enhanced interaction with viral spike protein, its thermal stability was increased, and its enzymatic function was inhibited as a decoy receptor. Moreover, the mACE2 protein showed higher efficacy in the neutralization of the SARS-CoV-2. In conclusion, this study proposes a novel approach with potential benefits such as targeted drug delivery and reduced side effects on healthy tissues. These transduced MSCs can also be used in combination with other anti-COVID-19 treatments. Design of similar engineered biomolecules with desired properties could also be used to target other diseases.
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Affiliation(s)
- Zahra Sadat Hashemi
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
| | - Saeed Khalili
- Department of Biology Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran.
| | | | | | - Hassan Sanati
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | | | - Mohammad Javad Rasaee
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Pourya Nasirmoghadas
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Kim YS, Kim M, Park HM, Kim HJ, Ryu SE. Disulfide Bond Engineering of Soluble ACE2 for Thermal Stability Enhancement. Int J Mol Sci 2024; 25:9919. [PMID: 39337407 PMCID: PMC11432317 DOI: 10.3390/ijms25189919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Revised: 09/11/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
Although the primary pandemic of SARS-CoV-2 is over, there are concerns about the resurgence of the next wave of related viruses, including a wide range of variant viruses. The soluble ACE2 (sACE2) inhibits the SARS-CoV-2 spike protein ACE2 interaction and has potential as a variant-independent therapeutic against SARS-CoV-2. Here, we introduce novel disulfide bonds in the wild-type sACE2-Fc by structure-guided mutagenesis, aiming to improve its stability. The stability of each mutant was assessed by a thermal shift assay to screen mutants with increased thermal stability. As a result, we identified a mutant sACE2-Fc with a significantly increased melting temperature. X-ray crystal structure determination of the sACE2 mutant confirmed the correct formation of the designed disulfide bond, and there were no significant structural disturbances. We also proved that the thermostable sACE2-Fc preserved the spike protein binding affinity comparable to the wild-type sACE2-Fc in both molecular and cellular environments, suggesting its therapeutic potential.
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Affiliation(s)
- Yoon Soo Kim
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04673, Republic of Korea
| | - Myeongbin Kim
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04673, Republic of Korea
| | - Hye Min Park
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04673, Republic of Korea
| | - Hyun Jin Kim
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04673, Republic of Korea
| | - Seong Eon Ryu
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04673, Republic of Korea
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Shirazi M, Cianfarini C, Ismail A, Wysocki J, Wang JJ, Ye M, Zhang ZJ, Batlle D. Altered kidney distribution and loss of ACE2 into the urine in acute kidney injury. Am J Physiol Renal Physiol 2024; 327:F412-F425. [PMID: 38961845 PMCID: PMC11460339 DOI: 10.1152/ajprenal.00237.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 05/28/2024] [Accepted: 06/17/2024] [Indexed: 07/05/2024] Open
Abstract
There are diverse pathophysiological mechanisms involved in acute kidney injury (AKI). Among them, overactivity of the renin-angiotensin system (RAS) has been described. Angiotensin-converting enzyme 2 (ACE2) is a tissue RAS enzyme expressed in the apical border of proximal tubules. Given the important role of ACE2 in the metabolism of angiotensin II, this study aimed to characterize kidney and urinary ACE2 in a mouse model of AKI. Ischemia-reperfusion injury (IRI) was induced in C57BL/6 mice by clamping of the left renal artery followed by removal of the right kidney. In kidneys harvested 48 h after IRI, immunostaining revealed a striking maldistribution of ACE2 including spillage into the tubular lumen and the presence of ACE2-positive luminal casts in the medulla. In cortical membranes, ACE2 protein and enzymatic activity were both markedly reduced (37 ± 4 vs. 100 ± 6 ACE2/β-actin, P = 0.0004, and 96 ± 14 vs. 152 ± 6 RFU/μg protein/h, P = 0.006). In urine, full-length membrane-bound ACE2 protein (100 kDa) was markedly increased (1,120 ± 405 vs. 100 ± 46 ACE2/µg creatinine, P = 0.04), and casts stained for ACE2 were recovered in the urine sediment. In conclusion, in AKI caused by IRI, there is a marked loss of ACE2 from the apical tubular border with deposition of ACE2-positive material in the medulla and increased urinary excretion of full-length membrane-bound ACE2 protein. The deficiency of tubular ACE2 in AKI suggests that provision of this enzyme could have therapeutic applications and that its excretion in the urine may also serve as a diagnostic marker of severe proximal tubular injury.NEW & NOTEWORTHY This study provides novel insights into the distribution of kidney ACE2 in a model of AKI by IRI showing a striking detachment of apical ACE2 from proximal tubules and its loss in urine and urine sediment. The observed deficiency of kidney ACE2 protein and enzymatic activity in severe AKI suggests that administration of forms of this enzyme may mitigate AKI and that urinary ACE2 may serve as a potential biomarker for tubular injury.
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Affiliation(s)
- Mina Shirazi
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
- Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Cosimo Cianfarini
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
- Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Ahmed Ismail
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
| | - Jan Wysocki
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
| | - Jiao-Jing Wang
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
| | - Minghao Ye
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
| | - Zheng Jenny Zhang
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
| | - Daniel Batlle
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
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Jiang H, Liu M, Yang W, Hong YK, Xu D, Nalbant EK, Clutter ED, Foroozandeh P, Kaplan N, Wysocki J, Batlle D, Miller SD, Lu K, Peng H. Activation of limbal epithelial proliferation is partly controlled by the ACE2-LCN2 pathway. iScience 2024; 27:110534. [PMID: 39175771 PMCID: PMC11338997 DOI: 10.1016/j.isci.2024.110534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 05/19/2024] [Accepted: 07/15/2024] [Indexed: 08/24/2024] Open
Abstract
In response to corneal injury, an activation of corneal epithelial stem cells and their direct progeny the early transit amplifying (eTA) cells to rapidly proliferate is critical for proper re-epithelialization. Thus, it is important to understand how such stem/eTA cell activation is regulated. Angiotensin-converting enzyme 2 (ACE2) is predominantly expressed in the stem/eTA-enriched limbal epithelium but its role in the limbal epithelium was unclear. Single cell RNA sequencing (scRNA-seq) suggested that Ace2 involved the proliferation of the stem/eTA cells. Ace2 was reduced following corneal injury. Such reduction enhanced limbal epithelial proliferation and downregulated LCN2, a negative regulator of proliferation in a variety of tissues, via upregulating TGFA and consequently activating epidermal growth factor receptor (EGFR). Inhibition of EGFR or overexpression of LCN2 reversed the increased proliferation in limbal epithelial cells lacking ACE2. Our findings demonstrate that after corneal injury, ACE2 is downregulated, which activates limbal epithelial cell proliferation via a TGFA/EGFR/LCN2 pathway.
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Affiliation(s)
- Huimin Jiang
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- Department of Ophthalmology, The Second Hospital of Anhui Medical University, Hefei 230601, China
| | - Min Liu
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Wending Yang
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Yi-Kai Hong
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Dan Xu
- Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Elif Kayaalp Nalbant
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Elwin D. Clutter
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Parisa Foroozandeh
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Nihal Kaplan
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Jan Wysocki
- Medicine (Nephrology and Hypertension), Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Daniel Batlle
- Medicine (Nephrology and Hypertension), Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Stephen D. Miller
- Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Kurt Lu
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Han Peng
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
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Yamani F, Cianfarini C, Batlle D. Delayed Graft Function and the Renin-angiotensin System. Transplantation 2024; 108:1308-1318. [PMID: 38361243 PMCID: PMC11136607 DOI: 10.1097/tp.0000000000004934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
Delayed graft function (DGF) is a form of acute kidney injury (AKI) and a common complication following kidney transplantation. It adversely influences patient outcomes increases the financial burden of transplantation, and currently, no specific treatments are available. In developing this form of AKI, activation of the renin-angiotensin system (RAS) has been proposed to play an important role. In this review, we discuss the role of RAS activation and its contribution to the pathophysiology of DGF following the different stages of the transplantation process, from procurement and ischemia to transplantation into the recipient and including data from experimental animal models. Deceased kidney donors, whether during cardiac or brain death, may experience activation of the RAS. That may be continued or further potentiated during procurement and organ preservation. Additional evidence suggests that during implantation of the kidney graft and reperfusion in the recipient, the RAS is activated and may likely remain activated, extrapolating from other forms of AKI where RAS overactivity is well documented. Of particular interest in this setting is the status of angiotensin-converting enzyme 2, a key RAS enzyme essential for the metabolism of angiotensin II and abundantly present in the apical border of the proximal tubules, which is the site of predominant injury in AKI and DGF. Interventions aimed at safely downregulating the RAS using suitable shorter forms of angiotensin-converting enzyme 2 could be a way to offer protection against DGF.
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Affiliation(s)
- Fatmah Yamani
- Division of Nephrology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Cosimo Cianfarini
- Division of Nephrology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Daniel Batlle
- Division of Nephrology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
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Fan H, Shang N, Davidge ST, Wu J. Chicken Muscle-Derived ACE2-Upregulating Peptide VVHPKESF Reduces Blood Pressure Associated with the ACE2/Ang (1-7)/MasR Axis in Spontaneously Hypertensive Rats. Mol Nutr Food Res 2024; 68:e2300524. [PMID: 38356052 DOI: 10.1002/mnfr.202300524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 12/29/2023] [Indexed: 02/16/2024]
Abstract
SCOPE This study aims to investigate the antihypertensive effect of four chicken muscle-derived angiotensin (Ang)-converting enzymes (ACE)-regulating peptides: Val-Arg-Pro (VRP, ACE inhibition), Leu-Lys-Tyr and Val-Arg-Tyr (LKY and VRY, ACE inhibition and ACE2 upregulation), and Val-Val-His-Pro-Lys-Glu-Ser-Phe (VVHPKESF [V-F], ACE2 upregulation) in spontaneously hypertensive rats. METHODS AND RESULTS Rats (12-14 weeks old) are grouped: 1) untreated, 2) VRP, 3) LKY, 4) VRY, and 5) V-F. Blood pressure (BP) is monitored using implantable telemetry technology. Over 18-day oral administration of 15 mg kg-1 body weight (BW) per day, only peptide V-F significantly (p < 0.05) reduces BP, decreases circulating Ang II, and increases ACE2 and Ang (1-7) levels, and enhances aortic expressions of ACE2 and Mas receptor (MasR). Peptide V-F also attenuates vascular inflammation (TNFα, MCP-1, IL-1α, IL-15, and cyclooxygenase 2 [COX2]) and vascular oxidative stress (nitrotyrosine). The gastrointestinal (GI)-degraded fragment of peptide V-F, Val-Val-His-Pro-Lys (VVHPK), is also an ACE2-upregulating peptide. Peptides VRP, LKY, and VRY do not reduce BP, possibly due to low bioavailability or other unknown reasons. CONCLUSIONS Peptide V-F is the first ACE2-upregulating peptide, purified and fractionated from food proteins based on in vitro ACE2 upregulation, that reduces BP associated with the activation of ACE2/Ang (1-7)/MasR axis; the N-terminal moiety VVHPK may be responsible for the antihypertensive effect of V-F.
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Affiliation(s)
- Hongbing Fan
- Department of Agricultural, Food and Nutritional Science, University of Alberta, 4-10 Ag/For Building, Edmonton, Alberta, T6G 2P5, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, T6G 2R7, Canada
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY, 40546, USA
| | - Nan Shang
- Department of Agricultural, Food and Nutritional Science, University of Alberta, 4-10 Ag/For Building, Edmonton, Alberta, T6G 2P5, Canada
| | - Sandra T Davidge
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, T6G 2R7, Canada
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, T6G 2R7, Canada
- Department of Physiology, University of Alberta, Edmonton, Alberta, T6G 2R7, Canada
- Women and Children's Health Research Institute, University of Alberta, Edmonton, Alberta, T6G 2R7, Canada
| | - Jianping Wu
- Department of Agricultural, Food and Nutritional Science, University of Alberta, 4-10 Ag/For Building, Edmonton, Alberta, T6G 2P5, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, T6G 2R7, Canada
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Dilawari R, Chaubey GK, Modanwal R, Dhiman A, Talukdar S, Kumar A, Raje CI, Raje M. Glyceraldehyde-3-Phosphate Dehydrogenase Binds with Spike Protein and Inhibits the Entry of SARS-CoV-2 into Host Cells. J Innate Immun 2024; 16:133-142. [PMID: 38325356 PMCID: PMC10911789 DOI: 10.1159/000535634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 11/29/2023] [Indexed: 02/09/2024] Open
Abstract
INTRODUCTION Coronavirus disease 2019 caused by coronavirus-2 (SARS-CoV-2) has emerged as an aggressive viral pandemic. Health care providers confront a challenging task for rapid development of effective strategies to combat this and its long-term after effects. Virus entry into host cells involves interaction between receptor-binding domain (RBD) of spike (S) protein S1 subunit with angiotensin converting enzyme present on host cells. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a moonlighting enzyme involved in cellular glycolytic energy metabolism and micronutrient homeostasis. It is deployed in various cellular compartments and the extra cellular milieu. Though it is known to moonlight as a component of mammalian innate immune defense machinery, till date its role in viral restriction remains unknown. METHOD Recombinant S protein, the RBD, and human GAPDH protein were used for solid phase binding assays and biolayer interferometry. Pseudovirus particles expressing four different strain variants of S protein all harboring ZsGreen gene as marker of infection were used for flow cytometry-based infectivity assays. RESULTS Pseudovirus entry into target cells in culture was significantly inhibited by addition of human GAPDH into the extracellular medium. Binding assays demonstrated that human GAPDH binds to S protein and RBD of SARS-CoV-2 with nanomolar affinity. CONCLUSIONS Our investigations suggest that this interaction of GAPDH interferes in the viral docking with hACE2 receptors, thereby affecting viral ingress into mammalian cells.
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Affiliation(s)
- Rahul Dilawari
- Institute of Microbial Technology, CSIR, Chandigarh, India
| | | | | | - Asmita Dhiman
- Institute of Microbial Technology, CSIR, Chandigarh, India
| | | | - Ajay Kumar
- National Institute of Pharmaceutical Education and Research, Sahibzada Ajit Singh Nagar, India
| | - Chaaya Iyengar Raje
- National Institute of Pharmaceutical Education and Research, Sahibzada Ajit Singh Nagar, India
| | - Manoj Raje
- Institute of Microbial Technology, CSIR, Chandigarh, India
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Schmidt-Lauber C, Alba Schmidt E, Hänzelmann S, Petersen EL, Behrendt CA, Twerenbold R, Blankenberg S, Huber TB, Wenzel UO. Increased blood pressure after nonsevere COVID-19. J Hypertens 2023; 41:1721-1729. [PMID: 37682048 PMCID: PMC10552808 DOI: 10.1097/hjh.0000000000003522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 07/05/2023] [Accepted: 07/12/2023] [Indexed: 09/09/2023]
Abstract
BACKGROUND Various sequelae have been described after nonsevere coronavirus disease 2019 (COVID-19), but knowledge on postacute effects on blood pressure is limited. METHODS This is a cross-sectional analysis of blood pressure profiles in individuals after nonsevere COVID-19 compared with matched population-based individuals without prior COVID-19. Data were derived from the ongoing and prospective Hamburg City Health Study, a population-based study in Hamburg, Germany, and its associated COVID-19 program, which included individuals at least 4 months after COVID-19. Matching was performed by age, sex, education, and preexisting hypertension in a 1 : 4 ratio. RESULTS Four hundred and thirty-two individuals after COVID-19 (mean age 56.1 years) were matched to 1728 controls without prior COVID-19 (56.2 years). About 92.8% of COVID-19 courses were mild or moderate, only 7.2% were hospitalized, and no individual had been treated on an intensive care unit. Even after adjustment for relevant competing risk factors, DBP [+4.7 mmHg, 95% confidence interval (95% CI) 3.97-5.7, P < 0.001] was significantly higher in individuals after COVID-19. For SBP, a trend towards increased values was observed (+1.4 mmHg, 95% CI -0.4 to 3.2, P = 0.120). Hypertensive blood pressures at least 130/80 mmHg (according to the ACC/AHA guideline) and at least 140/90 mmHg (ESC/ESH guideline) occurred significantly more often in individuals after COVID-19 than matched controls (odds ratio 2.0, 95% CI 1.5-2.7, P < 0.001 and odds ratio 1.6, 95% CI 1.3-2.0, P < 0.001, respectively), mainly driven by changes in DBP. CONCLUSION Blood pressure is higher in individuals after nonsevere COVID-19 compared with uninfected individuals suggesting a significant hypertensive sequela.
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Affiliation(s)
- Christian Schmidt-Lauber
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf
- Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg
- Research Center On Rare Kidney Diseases (RECORD), University Hospital Erlangen, Erlangen
| | - Elisa Alba Schmidt
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf
- Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg
| | - Sonja Hänzelmann
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf
- Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg
- Institute of Medical Systems Biology, University Medical Center Hamburg-Eppendorf
| | - Elina L. Petersen
- Department of Cardiology, University Heart and Vascular Center, Hamburg
| | | | - Raphael Twerenbold
- Department of Cardiology, University Heart and Vascular Center, Hamburg
- University Center of Cardiovascular Science, University Medical Center Hamburg-Eppendorf, Hamburg
- German Center for Cardiovascular Research (DZHK), Partner Site Hamburg–Kiel–Lübeck, Germany
| | - Stefan Blankenberg
- Department of Cardiology, University Heart and Vascular Center, Hamburg
- University Center of Cardiovascular Science, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Tobias B. Huber
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf
- Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg
| | - Ulrich O. Wenzel
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf
- Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg
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12
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Naik R, Avula S, Palleti SK, Gummadi J, Ramachandran R, Chandramohan D, Dhillon G, Gill AS, Paiwal K, Shaik B, Balachandran M, Patel B, Gurugubelli S, Mariswamy Arun Kumar AK, Nanjundappa A, Bellamkonda M, Rathi K, Sakhamuri PL, Nassar M, Bali A. From Emergence to Endemicity: A Comprehensive Review of COVID-19. Cureus 2023; 15:e48046. [PMID: 37916248 PMCID: PMC10617653 DOI: 10.7759/cureus.48046] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/31/2023] [Indexed: 11/03/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), later renamed coronavirus disease 2019 (COVID-19), was first identified in Wuhan, China, in early December 2019. Initially, the China office of the World Health Organization was informed of numerous cases of pneumonia of unidentified etiology in Wuhan, Hubei Province at the end of 2019. This would subsequently result in a global pandemic with millions of confirmed cases of COVID-19 and millions of deaths reported to the WHO. We have analyzed most of the data published since the beginning of the pandemic to compile this comprehensive review of SARS-CoV-2. We looked at the core ideas, such as the etiology, epidemiology, pathogenesis, clinical symptoms, diagnostics, histopathologic findings, consequences, therapies, and vaccines. We have also included the long-term effects and myths associated with some therapeutics of COVID-19. This study presents a comprehensive assessment of the SARS-CoV-2 virology, vaccines, medicines, and significant variants identified during the course of the pandemic. Our review article is intended to provide medical practitioners with a better understanding of the fundamental sciences, clinical treatment, and prevention of COVID-19. As of May 2023, this paper contains the most recent data made accessible.
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Affiliation(s)
- Roopa Naik
- Medicine, Geisinger Commonwealth School of Medicine, Scranton, USA
- Internal Medicine/Hospital Medicine, Geisinger Health System, Wilkes Barre, USA
| | - Sreekant Avula
- Diabetes, Endocrinology, and Metabolism, University of Minnesota, Minneapolis, USA
| | - Sujith K Palleti
- Nephrology, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Jyotsna Gummadi
- Internal Medicine, MedStar Franklin Square Medical Center, Baltimore, USA
| | | | | | - Gagandeep Dhillon
- Physician Executive MBA, University of Tennessee, Knoxville, USA
- Internal Medicine, University of Maryland Baltimore Washington Medical Center, Glen Burnie, USA
| | | | - Kapil Paiwal
- Oral & Maxillofacial Pathology, Daswani Dental College & Research Center, Kota, IND
| | - Bushra Shaik
- Internal Medicine, Onslow Memorial Hospital, Jacksonville, USA
| | | | - Bhumika Patel
- Oral Medicine and Radiology, Howard University, Washington, D.C., USA
| | | | | | | | - Mahita Bellamkonda
- Hospital Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Kanika Rathi
- Internal Medicine, University of Florida, Gainesville, USA
| | | | - Mahmoud Nassar
- Endocrinology, Diabetes, and Metabolism, Jacobs School of Medicine and Biomedical Sciences, Buffalo, USA
| | - Atul Bali
- Internal Medicine/Nephrology, Geisinger Medical Center, Danville, USA
- Internal Medicine/Nephrology, Geisinger Health System, Wilkes-Barre, USA
- Medicine, Geisinger Commonwealth School of Medicine, Scranton, USA
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13
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Qiu H, Li J, Li J, Li H, Xin Y. COVID-19 and Acute Cardiac Injury: Clinical Manifestations, Biomarkers, Mechanisms, Diagnosis, and Treatment. Curr Cardiol Rep 2023; 25:817-829. [PMID: 37314650 DOI: 10.1007/s11886-023-01902-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/05/2023] [Indexed: 06/15/2023]
Abstract
PURPOSE OF REVIEW This review aims to comprehensively explore the clinical characteristics of COVID-19-related cardiac injury and examine the potential mechanisms underlying cardiac injury in patients affected by COVID-19. RECENT FINDINGS The COVID-19 pandemic has primarily been associated with severe respiratory symptoms. However, emerging evidence has indicated that a significant number of COVID-19 patients also experience myocardial injury, leading to conditions such as acute myocarditis, heart failure, acute coronary syndrome, and arrhythmias. The incidence of myocardial injury is notably higher in patients with preexisting cardiovascular diseases. Myocardial injury often manifests with elevated levels of inflammation biomarkers, as well as abnormalities observed on electrocardiograms and echocardiograms. COVID-19 infection has been found to be associated with myocardial injury, which can be attributed to several pathophysiological mechanisms. These mechanisms include injury caused by hypoxia, resulting from respiratory compromise, a systemic inflammatory response triggered by the infection, and direct attack on the myocardium by the virus itself. Furthermore, the angiotensin-converting enzyme 2 (ACE2) receptor plays a crucial role in this process. Early recognition, prompt diagnosis, and a comprehensive understanding of the underlying mechanisms are essential for effectively managing and reducing the mortality associated with myocardial injury in COVID-19 patients.
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Affiliation(s)
- Hui Qiu
- Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Cardiovascular Center, Beijing, China
| | - Jiayu Li
- Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Cardiovascular Center, Beijing, China
| | - Jingye Li
- Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Cardiovascular Center, Beijing, China
| | - Hongwei Li
- Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Cardiovascular Center, Beijing, China
- Beijing Key Laboratory of Metabolic Disorder Related Cardiovascular Disease, Beijing, China
| | - Yanguo Xin
- Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Cardiovascular Center, Beijing, China.
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14
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Hassler L, Wysocki J, Ahrendsen JT, Ye M, Gelarden I, Nicolaescu V, Tomatsidou A, Gula H, Cianfarini C, Forster P, Khurram N, Singer BD, Randall G, Missiakas D, Henkin J, Batlle D. Intranasal soluble ACE2 improves survival and prevents brain SARS-CoV-2 infection. Life Sci Alliance 2023; 6:e202301969. [PMID: 37041017 PMCID: PMC10098141 DOI: 10.26508/lsa.202301969] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/01/2023] [Accepted: 04/04/2023] [Indexed: 04/13/2023] Open
Abstract
A soluble ACE2 protein bioengineered for long duration of action and high affinity to SARS-CoV-2 was administered either intranasally (IN) or intraperitoneally (IP) to SARS-CoV-2-inoculated k18hACE2 mice. This decoy protein (ACE2 618-DDC-ABD) was given either IN or IP, pre- and post-inoculation, or IN, IP, or IN + IP but only post-inoculation. Survival by day 5 was 0% in untreated mice, 40% in the IP-pre, and 90% in the IN-pre group. In the IN-pre group, brain histopathology was essentially normal and lung histopathology significantly improved. Consistent with this, brain SARS-CoV-2 titers were undetectable and lung titers reduced in the IN-pre group. When ACE2 618-DDC-ABD was administered only post-inoculation, survival was 30% in the IN + IP, 20% in the IN, and 20% in the IP group. We conclude that ACE2 618-DDC-ABD results in markedly improved survival and provides organ protection when given intranasally as compared with when given either systemically or after viral inoculation, and that lowering brain titers is a critical determinant of survival and organ protection.
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Affiliation(s)
- Luise Hassler
- Division of Nephrology/Hypertension, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
- Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Jan Wysocki
- Division of Nephrology/Hypertension, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - Jared T Ahrendsen
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - Minghao Ye
- Division of Nephrology/Hypertension, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - Ian Gelarden
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - Vlad Nicolaescu
- Department of Microbiology, University of Chicago, Chicago, IL, USA
- Ricketts Regional Biocontainment Laboratory, University of Chicago, Lemont, IL, USA
| | - Anastasia Tomatsidou
- Department of Microbiology, University of Chicago, Chicago, IL, USA
- Ricketts Regional Biocontainment Laboratory, University of Chicago, Lemont, IL, USA
| | - Haley Gula
- Department of Microbiology, University of Chicago, Chicago, IL, USA
- Ricketts Regional Biocontainment Laboratory, University of Chicago, Lemont, IL, USA
| | - Cosimo Cianfarini
- Division of Nephrology/Hypertension, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - Peter Forster
- Division of Nephrology/Hypertension, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - Nigar Khurram
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - Benjamin D Singer
- Division of Pulmonary and Critical Care Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - Glenn Randall
- Department of Microbiology, University of Chicago, Chicago, IL, USA
- Ricketts Regional Biocontainment Laboratory, University of Chicago, Lemont, IL, USA
| | - Dominique Missiakas
- Department of Microbiology, University of Chicago, Chicago, IL, USA
- Ricketts Regional Biocontainment Laboratory, University of Chicago, Lemont, IL, USA
| | - Jack Henkin
- Center for Developmental Therapeutics, Northwestern University, Evanston, IL, USA
| | - Daniel Batlle
- Division of Nephrology/Hypertension, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
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15
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Alkhaldi SY, Peng I, Peng CA. Inhibition of SARS-CoV-2 Spike Protein Pseudotyped Virus Infection Using ACE2-Tethered Micro/Nanoparticles. Bioengineering (Basel) 2023; 10:652. [PMID: 37370582 PMCID: PMC10294827 DOI: 10.3390/bioengineering10060652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/22/2023] [Accepted: 05/23/2023] [Indexed: 06/29/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) has caused a global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The viral infection is reliant upon the binding between angiotensin-converting enzyme 2 receptor (ACE2) and spike protein (S). Therefore, ACE2 is a key receptor for SARS-CoV-2 to infect the host. Nonetheless, as SARS-CoV-2 is constantly mutating into new variants that cause high infection rates, the development of prophylactic and therapeutic approaches remains a necessity to continue fighting mutated SARS-CoV-2 variants. In this study, ACE2-streptavidin fusion proteins expressed by recombinant DNA technology were anchored on biotinylated fluorescent polystyrene particles of various sizes ranging from 0.15 to 5 µm. The ACE2-tethered micro/nanoparticles were shown to prevent spike protein pseudotyped lentivirus entry into ACE2-expressing HEK293T cells. Compared to ACE2 in soluble form, micro-sized particles (2 and 5 µm) immobilized with ACE2 interfered more efficiently with viral attachment, entry, and the ensuing infection. Our results showed that particles functionalized with ACE2 could be used as efficient decoys to block the infection of SARS-CoV-2 strains.
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Affiliation(s)
| | | | - Ching-An Peng
- Department of Chemical and Biological Engineering, University of Idaho, Moscow, ID 83844, USA
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16
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Guimarães VHD, Marinho BM, Motta-Santos D, Mendes GDRL, Santos SHS. Nutritional implications in the mechanistic link between the intestinal microbiome, renin-angiotensin system, and the development of obesity and metabolic syndrome. J Nutr Biochem 2023; 113:109252. [PMID: 36509338 DOI: 10.1016/j.jnutbio.2022.109252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 11/12/2022] [Accepted: 12/07/2022] [Indexed: 12/13/2022]
Abstract
Obesity and metabolic disorders represent a significant global health problem and the gut microbiota plays an important role in modulating systemic homeostasis. Recent evidence shows that microbiota and its signaling pathways may affect the whole metabolism and the Renin-Angiotensin System (RAS), which in turn seems to modify microbiota. The present review aimed to investigate nutritional implications in the mechanistic link between the intestinal microbiome, renin-angiotensin system, and the development of obesity and metabolic syndrome components. A description of metabolic changes was obtained based on relevant scientific literature. The molecular and physiological mechanisms that impact the human microbiome were addressed, including the gut microbiota associated with obesity, diabetes, and hepatic steatosis. The RAS interaction signaling and modulation were analyzed. Strategies including the use of prebiotics, symbiotics, probiotics, and biotechnology may affect the gut microbiota and its impact on human health.
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Affiliation(s)
- Victor Hugo Dantas Guimarães
- Laboratory of Health Science, Postgraduate Program in Health Science, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brazil
| | - Barbhara Mota Marinho
- Laboratory of Health Science, Postgraduate Program in Health Science, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brazil
| | - Daisy Motta-Santos
- School of Physical Education, Physiotherapy, and Occupational Therapy - EEFFTO, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
| | - Gabriela da Rocha Lemos Mendes
- Food Engineering, Institute of Agricultural Sciences (ICA), Universidade Federal de Minas Gerais (UFMG), Montes Claros, Minas Gerais, Brazil
| | - Sérgio Henrique Sousa Santos
- Laboratory of Health Science, Postgraduate Program in Health Science, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brazil; Food Engineering, Institute of Agricultural Sciences (ICA), Universidade Federal de Minas Gerais (UFMG), Montes Claros, Minas Gerais, Brazil.
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17
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Angeli F, Zappa M, Reboldi G, Gentile G, Trapasso M, Spanevello A, Verdecchia P. The spike effect of acute respiratory syndrome coronavirus 2 and coronavirus disease 2019 vaccines on blood pressure. Eur J Intern Med 2023; 109:12-21. [PMID: 36528504 PMCID: PMC9744686 DOI: 10.1016/j.ejim.2022.12.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 12/07/2022] [Accepted: 12/12/2022] [Indexed: 12/14/2022]
Abstract
Among the various comorbidities potentially worsening the clinical outcome in patients hospitalized for the acute respiratory syndrome coronavirus-2 (SARS-CoV-2), hypertension is one of the most prevalent. However, the basic mechanisms underlying the development of severe forms of coronavirus disease 2019 (COVID-19) among hypertensive patients remain undefined and the direct association of hypertension with outcome in COVID-19 is still a field of debate. Experimental and clinical data suggest that SARS-CoV-2 infection promotes a rise in blood pressure (BP) during the acute phase of infection. Acute increase in BP and high in-hospital BP variability may be tied with acute organ damage and a worse outcome in patients hospitalized for COVID-19. In this context, the failure of the counter-regulatory renin-angiotensin-system (RAS) axis is a potentially relevant mechanism involved in the raise in BP. It is well recognized that the efficient binding of the Spike (S) protein to angiotensin converting enzyme 2 (ACE2) receptors mediates the virus entry into cells. Internalization of ACE2, downregulation and malfunction predominantly due to viral occupation, dysregulates the protective RAS axis with increased generation and activity of angiotensin (Ang) II and reduced formation of Ang1,7. Thus, the imbalance between Ang II and Ang1-7 can directly contribute to excessively rise BP in the acute phase of SARS-CoV-2 infection. A similar mechanism has been postulated to explain the raise in BP following COVID-19 vaccination ("Spike Effect" similar to that observed during the infection of SARS-CoV-2). S proteins produced upon vaccination have the native-like mimicry of SARS-CoV-2 S protein's receptor binding functionality and prefusion structure and free-floating S proteins released by the destroyed cells previously targeted by vaccines may interact with ACE2 of other cells, thereby promoting ACE2 internalization and degradation, and loss of ACE2 activities.
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Affiliation(s)
- Fabio Angeli
- Department of Medicine and Surgery, University of Insubria, Varese, 21100, Italy; Department of Medicine and Cardiopulmonary Rehabilitation, Maugeri Care and Research Institute, IRCCS Tradate, 21049, Italy.
| | - Martina Zappa
- Department of Medicine and Surgery, University of Insubria, Varese, 21100, Italy
| | - Gianpaolo Reboldi
- Department of Medicine, and Centro di Ricerca Clinica e Traslazionale (CERICLET), University of Perugia, Perugia, 06100, Italy
| | - Giorgio Gentile
- College of Medicine and Health. University of Exeter, Exeter, United Kingdom and Department of Nephrology, Royal Cornwall Hospitals NHS Trust, Truro, United Kingdom
| | - Monica Trapasso
- Dipartimento di Igiene e Prevenzione Sanitaria, PSAL, Sede Territoriale di Varese, ATS Insubria, Varese, 21100, Italy
| | - Antonio Spanevello
- Department of Medicine and Surgery, University of Insubria, Varese, 21100, Italy; Department of Medicine and Cardiopulmonary Rehabilitation, Maugeri Care and Research Institute, IRCCS Tradate, 21049, Italy
| | - Paolo Verdecchia
- Division of Cardiology, Hospital S. Maria della Misericordia, Perugia, and Fondazione Umbra Cuore e Ipertensione-ONLUS, Perugia, 06100, Italy
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18
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Chen H, Peng J, Wang T, Wen J, Chen S, Huang Y, Zhang Y. Counter-regulatory renin-angiotensin system in hypertension: Review and update in the era of COVID-19 pandemic. Biochem Pharmacol 2023; 208:115370. [PMID: 36481346 PMCID: PMC9721294 DOI: 10.1016/j.bcp.2022.115370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/26/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
Cardiovascular disease is the major cause of mortality and disability, with hypertension being the most prevalent risk factor. Excessive activation of the renin-angiotensin system (RAS) under pathological conditions, leading to vascular remodeling and inflammation, is closely related to cardiovascular dysfunction. The counter-regulatory axis of the RAS consists of angiotensin-converting enzyme 2 (ACE2), angiotensin (1-7), angiotensin (1-9), alamandine, proto-oncogene Mas receptor, angiotensin II type-2 receptor and Mas-related G protein-coupled receptor member D. Each of these components has been shown to counteract the effects of the overactivated RAS. In this review, we summarize the latest insights into the complexity and interplay of the counter-regulatory RAS axis in hypertension, highlight the pathophysiological functions of ACE2, a multifunctional molecule linking hypertension and COVID-19, and discuss the function and therapeutic potential of targeting this counter-regulatory RAS axis to prevent and treat hypertension in the context of the current COVID-19 pandemic.
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Affiliation(s)
- Hongyin Chen
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen 518000, Guangdong, China
| | - Jiangyun Peng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, China,Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan 528200, Guangdong, China
| | - Tengyao Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, China,Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan 528200, Guangdong, China
| | - Jielu Wen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, China,Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan 528200, Guangdong, China
| | - Sifan Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, China,Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan 528200, Guangdong, China
| | - Yu Huang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China,Corresponding authors
| | - Yang Zhang
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen 518000, Guangdong, China,Corresponding authors
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19
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Bru S, González-Marrón A, Lidón-Moyano C, Carballar R, Martínez-Láinez JM, Pérez-Martín H, Fu M, Pérez-Ortuño R, Ballbè M, Pascual JA, Fernández E, Clotet J, Martínez-Sánchez JM. Determination of soluble angiotensin-converting enzyme 2 in saliva samples and its association with nicotine. ENVIRONMENTAL RESEARCH 2023; 216:114443. [PMID: 36195157 PMCID: PMC9527194 DOI: 10.1016/j.envres.2022.114443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 09/23/2022] [Accepted: 09/24/2022] [Indexed: 06/16/2023]
Abstract
INTRODUCTION The Angiotensin-Converting Enzyme 2 (ACE2) is the main receptor of the SARS-CoV-2. There is contradictory evidence on how the exposure to nicotine may module the concentration of soluble ACE2 (sACE2). The aim of this study was to assess the association between nicotine and sACE2 concentrations in saliva samples. METHODS Pooled analysis performed with data retrieved from two studies (n = 634 and n = 302). Geometric mean (GM) concentrations of sACE2, both total and relative to the total amount of protein in the sample, were compared according to sociodemographic variables and variables associated to nicotine. Multivariable linear regression models were fitted to explore the associations of sACE2 with nicotine adjusting for sex, age and body mass index. Spearman's rank-correlation coefficients were estimated between the concentrations of nicotine and cotinine, and pack-years, the concentration of relative sACE2 and the isoforms of sACE2. RESULTS We observed a significant increase of 0.108‰ and 0.087 ng/μl in the relative and absolute salivary sACE2 GM concentrations, respectively, between the lowest and highest nicotine levels. Similar results were observed for cotinine. These associations did not change in the multivariable linear models. There was a low correlation of nicotine and cotinine concentration with the concentration of relative salivary sACE2 (rs = 0.153 and rs = 0.132, respectively), pack-years (rs = 0.222 and rs = 0.235, respectively) and with the concentration of isoform 40 KDa (rs = 0.193 and rs = 0.140, respectively). CONCLUSION Salivary nicotine concentration seems to be limitedly associated with the concentration of sACE2.
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Affiliation(s)
- Samuel Bru
- Department of Basic Sciences, Universitat Internacional de Catalunya, Sant Cugat Del Vallès, Barcelona, Spain
| | - Adrián González-Marrón
- Group of Evaluation of Health Determinants and Health Policies, Department of Basic Sciences, Universitat Internacional de Catalunya, Sant Cugat Del Vallès, Barcelona, Spain
| | - Cristina Lidón-Moyano
- Group of Evaluation of Health Determinants and Health Policies, Department of Basic Sciences, Universitat Internacional de Catalunya, Sant Cugat Del Vallès, Barcelona, Spain
| | - Reyes Carballar
- Department of Basic Sciences, Universitat Internacional de Catalunya, Sant Cugat Del Vallès, Barcelona, Spain
| | - Joan Marc Martínez-Láinez
- Department of Basic Sciences, Universitat Internacional de Catalunya, Sant Cugat Del Vallès, Barcelona, Spain
| | - Hipólito Pérez-Martín
- Group of Evaluation of Health Determinants and Health Policies, Department of Basic Sciences, Universitat Internacional de Catalunya, Sant Cugat Del Vallès, Barcelona, Spain
| | - Marcela Fu
- Tobacco Control Unit, Catalan Institute of Oncology - ICO, WHO Collaborating Centre for Tobacco Control, L'Hospitalet de Llobregat, Barcelona, Spain; Tobacco Control Research Group, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain; School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Raúl Pérez-Ortuño
- Group of Integrative Pharmacology and Systems Neuroscience, Neurosciences Programme, IMIM (Hospital Del Mar Medical Research Institute), Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain
| | - Montse Ballbè
- Tobacco Control Unit, Catalan Institute of Oncology - ICO, WHO Collaborating Centre for Tobacco Control, L'Hospitalet de Llobregat, Barcelona, Spain; Tobacco Control Research Group, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain; Addictions Unit, Institute of Neurosciences, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Jose A Pascual
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona Biomedical Research Park, Barcelona, Spain
| | - Esteve Fernández
- Tobacco Control Unit, Catalan Institute of Oncology - ICO, WHO Collaborating Centre for Tobacco Control, L'Hospitalet de Llobregat, Barcelona, Spain; Tobacco Control Research Group, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain; School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Josep Clotet
- Department of Basic Sciences, Universitat Internacional de Catalunya, Sant Cugat Del Vallès, Barcelona, Spain.
| | - Jose M Martínez-Sánchez
- Group of Evaluation of Health Determinants and Health Policies, Department of Basic Sciences, Universitat Internacional de Catalunya, Sant Cugat Del Vallès, Barcelona, Spain.
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20
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Li J, Yan Y, Dou F, Gao J. Is targeting angiotensin-converting enzyme 2 (ACE2) a prophylactic strategy against COVID-19? Biosci Trends 2022; 16:459-461. [PMID: 36567123 DOI: 10.5582/bst.2022.01524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Prophylaxis against COVID-19 is greatly needed for vulnerable populations who have a higher risk of developing severe disease. Vaccines and neutralizing antibodies against SARS-CoV-2 are currently the main approaches to preventing the virus infection. However, the constant mutation of SARS-CoV-2 poses a huge challenge to the effectiveness of these prophylactic strategies. A recent study suggested that downregulation of angiotensin-converting enzyme 2 (ACE2), the receptor of SARS-CoV-2 entry into human cells, can decrease susceptibility to viral infection in vitro, in vivo, and in human lungs and livers perfused ex situ. These findings indicate the potential to use agents to reduce ACE2 expression to prevent COVID-19, but the efficacy and safety should be verified in clinical trials. Considering ACE2 performs physiological functions, risks due to its downregulation and benefits from prophylaxis against SARS-CoV-2 infection should be carefully weighed. In the future, updating vaccines against variants of SARS-CoV-2 might still be an important strategy for prophylaxis against COVID-19. Soluble recombinant human ACE2 that acts as a decoy receptor might be an option to overcome the mutation of SARS-CoV-2.
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Affiliation(s)
- Jing Li
- Department of Pharmacology, School of Pharmacy, Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
| | - Yufen Yan
- Department of Outpatient and Emergency, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Fangzhou Dou
- Department of Pharmacology, School of Pharmacy, Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
| | - Jianjun Gao
- Department of Pharmacology, School of Pharmacy, Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
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21
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Kim J, Jozic A, Mukherjee A, Nelson D, Chiem K, Khan MSR, Torrelles JB, Martinez‐Sobrido L, Sahay G. Rapid Generation of Circulating and Mucosal Decoy Human ACE2 using mRNA Nanotherapeutics for the Potential Treatment of SARS-CoV-2. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2202556. [PMID: 36216580 PMCID: PMC9762296 DOI: 10.1002/advs.202202556] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 09/19/2022] [Indexed: 05/24/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause lethal pulmonary damage in humans. It contains spike proteins on its envelope that bind to human angiotensin-converting enzyme 2 (hACE2) expressed on airway cells, enabling entry of the virus, and causing infection. The soluble form of hACE2 binds SARS-CoV-2 spike protein, prevents viral entry into target cells, and ameliorates lung injury; however, its short half-life limits therapeutic utilities. Here, synthetic mRNA is engineered to encode a soluble form of hACE2 (hsACE2) to prevent viral infection. A novel lipid nanoparticle (LNP) is used for packaging and delivering mRNA to cells to produce hsACE2 proteins. Intravenously administered LNP delivers mRNA to hepatocytes, leading to the production of circulatory hsACE2 initiated within 2 h and sustained over several days. Inhaled LNP results in lung transfection and secretion of mucosal hsACE2 to lung epithelia, the primary site of entry and pathogenesis for SARS-CoV-2. Furthermore, mRNA-generated hsACE2 binds to the receptor-binding domain of the viral spike protein. Finally, hsACE2 effectively inhibits SARS-CoV-2 and its pseudoviruses from infecting host cells. The proof of principle study shows that mRNA-based nanotherapeutics can be potentially deployed to neutralize SARS-CoV-2 and open new treatment opportunities for coronavirus disease 2019 (COVID-19).
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Affiliation(s)
- Jeonghwan Kim
- Department of Pharmaceutical SciencesCollege of PharmacyRobertson Life Sciences BuildingOregon State UniversityPortlandOR97201USA
| | - Antony Jozic
- Department of Pharmaceutical SciencesCollege of PharmacyRobertson Life Sciences BuildingOregon State UniversityPortlandOR97201USA
| | - Anindit Mukherjee
- Department of Pharmaceutical SciencesCollege of PharmacyRobertson Life Sciences BuildingOregon State UniversityPortlandOR97201USA
| | - Dylan Nelson
- Department of Pharmaceutical SciencesCollege of PharmacyRobertson Life Sciences BuildingOregon State UniversityPortlandOR97201USA
- High‐Throughput Screening Services LaboratoryCollege of PharmacyOregon State UniversityCorvallisOR97331USA
| | - Kevin Chiem
- Disease Prevention and Interventionand Population Health ProgramsTexas Biomedical Research InstituteSan AntonioTX78227USA
| | - Md Siddiqur Rahman Khan
- Disease Prevention and Interventionand Population Health ProgramsTexas Biomedical Research InstituteSan AntonioTX78227USA
| | - Jordi B. Torrelles
- Disease Prevention and Interventionand Population Health ProgramsTexas Biomedical Research InstituteSan AntonioTX78227USA
| | - Luis Martinez‐Sobrido
- Disease Prevention and Interventionand Population Health ProgramsTexas Biomedical Research InstituteSan AntonioTX78227USA
| | - Gaurav Sahay
- Department of Pharmaceutical SciencesCollege of PharmacyRobertson Life Sciences BuildingOregon State UniversityPortlandOR97201USA
- Department of Biomedical EngineeringRobertson Life Sciences BuildingOregon Health & Science UniversityPortlandOR97201USA
- Department of OphthalmologyCasey Eye InstituteOregon Health & Science UniversityPortlandOR97239USA
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22
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Silva-Aguiar RP, Teixeira DE, Peres RAS, Peruchetti DB, Gomes CP, Schmaier AH, Rocco PRM, Pinheiro AAS, Caruso-Neves C. Subclinical Acute Kidney Injury in COVID-19: Possible Mechanisms and Future Perspectives. Int J Mol Sci 2022; 23:ijms232214193. [PMID: 36430671 PMCID: PMC9693299 DOI: 10.3390/ijms232214193] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/14/2022] [Accepted: 11/15/2022] [Indexed: 11/18/2022] Open
Abstract
Since the outbreak of COVID-19 disease, a bidirectional interaction between kidney disease and the progression of COVID-19 has been demonstrated. Kidney disease is an independent risk factor for mortality of patients with COVID-19 as well as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leading to the development of acute kidney injury (AKI) and chronic kidney disease (CKD) in patients with COVID-19. However, the detection of kidney damage in patients with COVID-19 may not occur until an advanced stage based on the current clinical blood and urinary examinations. Some studies have pointed out the development of subclinical acute kidney injury (subAKI) syndrome with COVID-19. This syndrome is characterized by significant tubule interstitial injury without changes in the estimated glomerular filtration rate. Despite the complexity of the mechanism(s) underlying the development of subAKI, the involvement of changes in the protein endocytosis machinery in proximal tubule (PT) epithelial cells (PTECs) has been proposed. This paper focuses on the data relating to subAKI and COVID-19 and the role of PTECs and their protein endocytosis machinery in its pathogenesis.
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Affiliation(s)
- Rodrigo P. Silva-Aguiar
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil
| | - Douglas E. Teixeira
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil
| | - Rodrigo A. S. Peres
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil
| | - Diogo B. Peruchetti
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil
| | - Carlos P. Gomes
- Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil
- School of Medicine and Surgery, Federal University of the State of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil
| | - Alvin H. Schmaier
- Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
| | - Patricia R. M. Rocco
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, Brazil
- Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Rio de Janeiro 21045-900, Brazil
| | - Ana Acacia S. Pinheiro
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil
- Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Rio de Janeiro 21045-900, Brazil
| | - Celso Caruso-Neves
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, Brazil
- Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Rio de Janeiro 21045-900, Brazil
- Correspondence:
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23
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Mohammadi P, Varpaei HA, Seifi A, Zahak Miandoab S, Beiranvand S, Mobaraki S, Mohammadi M, Abdollahi A. Soluble ACE2 as a Risk or Prognostic Factor in COVID-19 Patients: A Cross-sectional Study. Med J Islam Repub Iran 2022; 36:135. [PMID: 36479537 PMCID: PMC9719580 DOI: 10.47176/mjiri.36.135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Indexed: 12/24/2022] Open
Abstract
Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel severe acute respiratory syndrome coronavirus. The first known receptor for this virus in the human body is angiotensin-converting enzyme 2 (ACE2), the same receptor for the SARS virus. Methods: A total of 38 hospitalized adult (18 years) patients with laboratory or clinically confirmed coronavirus disease 2019 (COVID-19) were identified in the infectious disease ward of Tehran Imam Khomeini hospital complex in this single-center cross-sectional study. A blood sample was taken at the time of hospitalization and a second one was taken 48 hours later. Blood samples are kept frozen at -80 degrees Celsius. After the complete collection of samples, the ACE2 level of the samples was measured using a serum sACE2 detection ELISA kit. The data were analyzed using SPSS v26. P value of 0.05 was considered statistically significant. An analysis of covariance was performed to examine the mean differences in day 7 serum ACE2 concentration among the 2 groups after adjusting for the baseline serum ACE2 concentration. The 1-way multivariate analysis of variance was used to determine whether there were any differences between independent groups (mechanical ventilation yes/no) on serum ACE2 levels at 3 different times. Results: The mean age of patients was 64.13 ± 16.49 years, 21 patients (55.3%) were men, 16 patients (42%) were polymerase chain reaction test positive, and 15 patients (39.5%) died. A total of 35 individuals (92.1%) had chest computed tomography images that indicated lung involvement. A comparison of the 2 groups of patients who died and were discharged revealed that serum ACE2 at the first (p=0.033) and third (7th day) measurements were statistically different (p=0.026). Patients had a mean of serum ACE2. The results indicated that the day 7 serum ACE2 concentration did significantly differ between the 2 groups after controlling for the baseline serum ACE2 concentration (p=0.023). The model explained about 73.61% of the variance in the 7-day serum ACE2 concentration. Specifically, after adjusting for the baseline concentration, survived patients had the lowest level of serum ACE2 concentration (1 ± 0.65) on the 7th day compared with the deceased patient group (2.83 ± 1.12). Conclusion: Soluble ACE2 in the serum of COVID-19 patients who died, later on, was significantly higher than the discharged patients when the samples were taken seven days after admission. It is suggested that serum soluble ACE2 level could be used as a prognostic factor for COVID-19 patients' outcomes and also their need for mechanical ventilation.
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Affiliation(s)
- Parsa Mohammadi
- Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Arash Seifi
- Department of Infectious Diseases, Tehran University of Medical Sciences, Imam Khomeini Hospital Complex, Tehran, Iran
| | - Sepideh Zahak Miandoab
- Department of Infectious Diseases, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Saba Beiranvand
- Department of Nursing, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Sahar Mobaraki
- Department of Nursing, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mostafa Mohammadi
- Tehran University of Medical Sciences, General ICU of Imam Khomeini Hospital Complex, Tehran, Iran, Corresponding author:Mostafa Mohammadi,
| | - Alireza Abdollahi
- Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
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24
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Axelerad A, Stuparu AZ, Muja LF, Docu Axelerad S, Petrov SG, Gogu AE, Jianu DC. Narrative Review of New Insight into the Influence of the COVID-19 Pandemic on Cardiovascular Care. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:1554. [PMID: 36363511 PMCID: PMC9694465 DOI: 10.3390/medicina58111554] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 10/21/2022] [Accepted: 10/26/2022] [Indexed: 09/10/2024]
Abstract
Background and Objectives: The purpose of this paper was to perform a literature review on the effects of the COVID-19 pandemic on cardiothoracic and vascular surgery care and departments. Materials and Methods: To conduct this evaluation, an electronic search of many databases was conducted, and the resulting papers were chosen and evaluated. Results: Firstly, we have addressed the impact of COVID-19 infection on the cardiovascular system from the pathophysiological and treatment points of view. Afterwards, we analyzed every cardiovascular disease that seemed to appear after a COVID-19 infection, emphasizing the treatment. In addition, we have analyzed the impact of the pandemic on the cardiothoracic and vascular departments in different countries and the transitions that appeared. Finally, we discussed the implications of the cardiothoracic and vascular specialists' and residents' work and studies on the pandemic. Conclusions: The global pandemic caused by SARS-CoV-2 compelled the vascular profession to review the treatment of certain vascular illnesses and find solutions to address the vascular consequences of COVID-19 infection. The collaboration between vascular surgeons, public health specialists, and epidemiologists must continue to investigate the impact of the pandemic and the response to the public health issue.
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Affiliation(s)
- Any Axelerad
- Department of Neurology, General Medicine Faculty, ‘Ovidius’ University, 900470 Constanta, Romania
- Department of Neurology, ‘Sf. Ap. Andrei’ County Clinical Emergency Hospital of Constanta, 900591 Constanta, Romania
| | - Alina Zorina Stuparu
- Department of Neurology, General Medicine Faculty, ‘Ovidius’ University, 900470 Constanta, Romania
- Department of Neurology, ‘Sf. Ap. Andrei’ County Clinical Emergency Hospital of Constanta, 900591 Constanta, Romania
| | - Lavinia Florenta Muja
- Department of Neurology, General Medicine Faculty, ‘Ovidius’ University, 900470 Constanta, Romania
- Department of Neurology, ‘Sf. Ap. Andrei’ County Clinical Emergency Hospital of Constanta, 900591 Constanta, Romania
| | | | - Silvia Georgeta Petrov
- Doctoral School of the Faculty of Psychology and Educational Sciences within the University of Bucharest, 050663 Bucharest, Romania
| | - Anca Elena Gogu
- Department of Neurology, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania
- Centre for Cognitive Research in Neuropsychiatric Pathology (Neuropsy-Cog), Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania
| | - Dragos Catalin Jianu
- Department of Neurology, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania
- Centre for Cognitive Research in Neuropsychiatric Pathology (Neuropsy-Cog), Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania
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25
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Peng I, Jokhio S, Alkhaldi S, Peng CA. Inactivation of SARS-CoV-2 Spike Protein Pseudotyped Virus Infection Using ACE2-Tethered Gold Nanorods under Near-Infrared Laser Irradiation. ACS APPLIED NANO MATERIALS 2022; 5:15942-15953. [PMID: 37552748 PMCID: PMC9578643 DOI: 10.1021/acsanm.2c04275] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 10/03/2022] [Indexed: 06/29/2023]
Abstract
Since the angiotensin-converting enzyme 2 (ACE2) protein is abundant on the surface of respiratory cells in the lungs, it has been confirmed to be the entry-point receptor for the spike glycoprotein of SARS-CoV-2. As such, gold nanorods (AuNRs) functionalized with ACE2 ectodomain (ACE2ED) act not only as decoys for these viruses to keep them from binding with the ACE2-expressing cells but also as agents to ablate infectious virions through heat generated from AuNRs under near-infrared (NIR) laser irradiation. Using plasmid containing the SARS-CoV-2 spike protein gene (with a D614G mutation), spike protein pseudotyped viral particles with a lentiviral core and green fluorescent protein reporter were constructed and used for transfecting ACE2-expressing HEK293T cells. Since these viral particles behave like their coronavirus counterparts, they are the ideal surrogates of native virions for studying viral entry into host cells. Our results showed that, once the surrogate pseudoviruses with spike protein encounter ACE2ED-tethered AuNRs, these virions are entrapped, resulting in decreased viral infection to ACE2-expressing HEK293T cells. Moreover, the effect of photothermolysis created by ACE2ED-tagged AuNRs under 808-nm NIR laser irradiation for 5 min led to viral breakdown. In summary, ACE2ED-tethered AuNRs with dual functions (virus decoy and destruction) could have an intriguing advantage in the treatment of diseases involving rapidly mutating viral species such as SARS-CoV-2.
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Affiliation(s)
- Ian Peng
- Department of Chemical and Biological Engineering,
University of Idaho, Moscow, Idaho83844, United
States
| | - Sharjeel Jokhio
- Department of Chemical and Biological Engineering,
University of Idaho, Moscow, Idaho83844, United
States
| | - Soha Alkhaldi
- Department of Chemical and Biological Engineering,
University of Idaho, Moscow, Idaho83844, United
States
| | - Ching-An Peng
- Department of Chemical and Biological Engineering,
University of Idaho, Moscow, Idaho83844, United
States
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26
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Obeng EM, Fianu I, Danquah MK. Multivalent ACE2 engineering-A promising pathway for advanced coronavirus nanomedicine development. NANO TODAY 2022; 46:101580. [PMID: 35942040 PMCID: PMC9350675 DOI: 10.1016/j.nantod.2022.101580] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/26/2022] [Accepted: 07/30/2022] [Indexed: 05/06/2023]
Abstract
The spread of coronavirus diseases has resulted in a clarion call to develop potent drugs and vaccines even as different strains appear beyond human prediction. An initial step that is integral to the viral entry into host cells results from an active-targeted interaction of the viral spike (S) proteins and the cell surface receptor, called angiotensin-converting enzyme 2 (ACE2). Thus, engineered ACE2 has been an interesting decoy inhibitor against emerging coronavirus infestation. This article discusses promising innovative ACE2 engineering pathways for current and emerging coronavirus therapeutic development. First, we provide a brief discussion of some ACE2-associated human coronaviruses and their cell invasion mechanism. Then, we describe and contrast the individual spike proteins and ACE2 receptor interactions, highlighting crucial hotspots across the ACE2-associated coronaviruses. Lastly, we address the importance of multivalency in ACE2 nanomedicine engineering and discuss novel approaches to develop and achieve multivalent therapeutic outcomes. Beyond coronaviruses, these approaches will serve as a paradigm to develop new and improved treatment technologies against pathogens that use ACE2 receptor for invasion.
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Affiliation(s)
- Eugene M Obeng
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
| | - Isaac Fianu
- Department of Molecular Biology, Max Planck Institute for Multidisciplinary Sciences, 37077 Göttingen, Germany
| | - Michael K Danquah
- Department of Chemical Engineering, University of Tennessee, 615 McCallie Ave, Chattanooga, TN 37403, United States
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27
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Angeli F, Reboldi G, Trapasso M, Zappa M, Spanevello A, Verdecchia P. COVID-19, vaccines and deficiency of ACE 2 and other angiotensinases. Closing the loop on the "Spike effect". Eur J Intern Med 2022; 103:23-28. [PMID: 35753869 PMCID: PMC9217159 DOI: 10.1016/j.ejim.2022.06.015] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Accepted: 06/20/2022] [Indexed: 11/03/2022]
Abstract
The role of a dysregulated renin-angiotensin system (RAS) in the pathogenesis of COVID-19 is well recognized. The imbalance between angiotensin II (Ang II) and Angiotensin1-7 (Ang1,7) caused by the interaction between SARS-CoV-2 and the angiotensin converting enzyme 2 (ACE2) receptors exerts a pivotal role on the clinical picture and outcome of COVID-19. ACE2 receptors are not the exclusive angiotensinases in nature. Other angiotensinases (PRCP, and POP) have the potential to limit the detrimental effects of the interactions between ACE2 and the Spike proteins. In the cardiovascular disease continuum, ACE2 activity tends to decrease, and POP/PRCP activity to increase, from the health status to advanced deterioration of the cardiovascular system. The failure of the counter-regulatory RAS axis during the acute phase of COVID-19 is characterized by a decrease of ACE2 expression coupled to unchanged activity of other angiotensinases, therefore failing to limit the accumulation of Ang II. COVID-19 vaccines increase the endogenous synthesis of SARS-CoV-2 spike proteins. Once synthetized, the free-floating spike proteins circulate in the blood, interact with ACE2 receptors and resemble the pathological features of SARS-CoV-2 ("Spike effect" of COVID-19 vaccines). It has been noted that an increased catalytic activity of POP/PRCP is typical in elderly individuals with comorbidities or previous cardiovascular events, but not in younger people. Thus, the adverse reactions to COVID-19 vaccination associated with Ang II accumulation are generally more common in younger and healthy subjects. Understanding the relationships between different mechanisms of Ang II cleavage and accumulation offers the opportunity to close the pathophysiological loop between the risk of progression to severe forms of COVID-19 and the potential adverse events of vaccination.
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Affiliation(s)
- Fabio Angeli
- Department of Medicine and Surgery, University of Insubria, Varese, Italy; Department of Medicine and Cardiopulmonary Rehabilitation, Maugeri Care and Research Institute, IRCCS, Tradate, Italy.
| | - Gianpaolo Reboldi
- Department of Medicine, and Centro di Ricerca Clinica e Traslazionale (CERICLET), University of Perugia, Perugia, Italy
| | - Monica Trapasso
- Dipartimento di Igiene e Prevenzione Sanitaria, ATS Insubria, PSAL, Sede Territoriale di Varese, Varese, Italy
| | - Martina Zappa
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Antonio Spanevello
- Department of Medicine and Surgery, University of Insubria, Varese, Italy; Department of Medicine and Cardiopulmonary Rehabilitation, Maugeri Care and Research Institute, IRCCS, Tradate, Italy
| | - Paolo Verdecchia
- Division of Cardiology, Hospital S. Maria Della Misericordia, Perugia, Italy; Fondazione Umbra Cuore e Ipertensione-ONLUS, Perugia, Italy
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28
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Norambuena-Soto I, Lopez-Crisosto C, Martinez-Bilbao J, Hernandez-Fuentes C, Parra V, Lavandero S, Chiong M. Angiotensin-(1-9) in hypertension. Biochem Pharmacol 2022; 203:115183. [PMID: 35870482 DOI: 10.1016/j.bcp.2022.115183] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/13/2022] [Accepted: 07/14/2022] [Indexed: 11/02/2022]
Abstract
Angiotensin-(1-9) [Ang-(1-9)] is a peptide of the non-canonical renin-angiotensin system (RAS) synthesized from angiotensin I by the monopeptidase angiotensin-converting enzyme type 2 (ACE2). Using osmotic minipumps, infusion of Ang-(1-9) consistently reduces blood pressure in several rat hypertension models. In these animals, hypertension-induced end-organ damage is also decreased. Several pieces of evidence suggest that Ang-(1-9) is the endogenous ligand that binds and activates the type-2 angiotensin II receptor (AT2R). Activation of AT2R triggers different tissue-specific signaling pathways. This phenomenon could be explained by the ability of AT2R to form different heterodimers with other G protein-coupled receptors. Because of the antihypertensive and protective effects of AT2R activation by Ang-(1-9), associated with a short half-life of RAS peptides, several synthetic AT2R agonists have been synthesized and assayed. Some of them, particularly CGP42112, C21 and novokinin, have demonstrated antihypertensive properties. Only two synthetic AT2R agonists, C21 and LP2-3, have been tested in clinical trials, but none of them like an antihypertensive. Therefore, Ang-(1-9) is a promising antihypertensive drug that reduces hypertension-induced end-organ damage. However, further research is required to translate this finding successfully to the clinic.
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Affiliation(s)
- Ignacio Norambuena-Soto
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical & Pharmaceutical Sciences and Faculty of Medicine, University of Chile, Santiago, Chile
| | - Camila Lopez-Crisosto
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical & Pharmaceutical Sciences and Faculty of Medicine, University of Chile, Santiago, Chile
| | - Javiera Martinez-Bilbao
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical & Pharmaceutical Sciences and Faculty of Medicine, University of Chile, Santiago, Chile
| | - Carolina Hernandez-Fuentes
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical & Pharmaceutical Sciences and Faculty of Medicine, University of Chile, Santiago, Chile
| | - Valentina Parra
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical & Pharmaceutical Sciences and Faculty of Medicine, University of Chile, Santiago, Chile; Network for the Study of High-lethality Cardiopulmonary Diseases (REECPAL), Universidad de Chile, Santiago, Chile
| | - Sergio Lavandero
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical & Pharmaceutical Sciences and Faculty of Medicine, University of Chile, Santiago, Chile; Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Mario Chiong
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical & Pharmaceutical Sciences and Faculty of Medicine, University of Chile, Santiago, Chile.
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29
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Lin H, Geurts F, Hassler L, Batlle D, Mirabito Colafella KM, Denton KM, Zhuo JL, Li XC, Ramkumar N, Koizumi M, Matsusaka T, Nishiyama A, Hoogduijn MJ, Hoorn EJ, Danser AHJ. Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting. Pharmacol Rev 2022; 74:462-505. [PMID: 35710133 PMCID: PMC9553117 DOI: 10.1124/pharmrev.120.000236] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The concept of local formation of angiotensin II in the kidney has changed over the last 10-15 years. Local synthesis of angiotensinogen in the proximal tubule has been proposed, combined with prorenin synthesis in the collecting duct. Binding of prorenin via the so-called (pro)renin receptor has been introduced, as well as megalin-mediated uptake of filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, angiotensin metabolites other than angiotensin II [notably angiotensin-(1-7)] exist, and angiotensins exert their effects via three different receptors, of which angiotensin II type 2 and Mas receptors are considered renoprotective, possibly in a sex-specific manner, whereas angiotensin II type 1 (AT1) receptors are believed to be deleterious. Additionally, internalized angiotensin II may stimulate intracellular receptors. Angiotensin-converting enzyme 2 (ACE2) not only generates angiotensin-(1-7) but also acts as coronavirus receptor. Multiple, if not all, cardiovascular diseases involve the kidney RAS, with renal AT1 receptors often being claimed to exert a crucial role. Urinary RAS component levels, depending on filtration, reabsorption, and local release, are believed to reflect renal RAS activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) and novel drugs (angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter-2 inhibitors, soluble ACE2) affect renal angiotensin formation, thereby displaying cardiovascular efficacy. Particular in the case of the latter three, an important question is to what degree they induce renoprotection (e.g., in a renal RAS-dependent manner). This review provides a unifying view, explaining not only how kidney angiotensin formation occurs and how it is affected by drugs but also why drugs are renoprotective when altering the renal RAS. SIGNIFICANCE STATEMENT: Angiotensin formation in the kidney is widely accepted but little understood, and multiple, often contrasting concepts have been put forward over the last two decades. This paper offers a unifying view, simultaneously explaining how existing and novel drugs exert renoprotection by interfering with kidney angiotensin formation.
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Affiliation(s)
- Hui Lin
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Frank Geurts
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Luise Hassler
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Daniel Batlle
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Katrina M Mirabito Colafella
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Kate M Denton
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Jia L Zhuo
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Xiao C Li
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Nirupama Ramkumar
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Masahiro Koizumi
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Taiji Matsusaka
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Akira Nishiyama
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Martin J Hoogduijn
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Ewout J Hoorn
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - A H Jan Danser
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
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30
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Hassler L, Wysocki J, Gelarden I, Sharma I, Tomatsidou A, Ye M, Gula H, Nicoleascu V, Randall G, Pshenychnyi S, Khurram N, Kanwar Y, Missiakas D, Henkin J, Yeldandi A, Batlle D. A Novel Soluble ACE2 Protein Provides Lung and Kidney Protection in Mice Susceptible to Lethal SARS-CoV-2 Infection. J Am Soc Nephrol 2022; 33:1293-1307. [PMID: 35236774 PMCID: PMC9257820 DOI: 10.1681/asn.2021091209] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 02/06/2022] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) uses full-length angiotensin converting enzyme 2 (ACE2) as a main receptor to enter target cells. The goal of this study was to demonstrate the preclinical efficacy of a novel soluble ACE2 protein with increased duration of action and binding capacity in a lethal mouse model of COVID-19. METHODS A human soluble ACE2 variant fused with an albumin binding domain (ABD) was linked via a dimerization motif hinge-like 4-cysteine dodecapeptide (DDC) to improve binding capacity to SARS-CoV-2. This novel soluble ACE2 protein (ACE2-1-618-DDC-ABD) was then administered intranasally and intraperitoneally to mice before intranasal inoculation of SARS-CoV-2 and then for two additional days post viral inoculation. RESULTS Untreated animals became severely ill, and all had to be humanely euthanized by day 6 or 7 and had pulmonary alveolar hemorrhage with mononuclear infiltrates. In contrast, all but one mouse infected with a lethal dose of SARS-CoV-2 that received ACE2-1-618-DDC-ABD survived. In the animals inoculated with SARS-CoV-2 that were untreated, viral titers were high in the lungs and brain, but viral titers were absent in the kidneys. Some untreated animals, however, had variable degrees of kidney proximal tubular injury as shown by attenuation of the proximal tubular brush border and increased NGAL and TUNEL staining. Viral titers in the lung and brain were reduced or nondetectable in mice that received ACE2-1-618-DDC-ABD, and the animals developed only moderate disease as assessed by a near-normal clinical score, minimal weight loss, and improved lung and kidney injury. CONCLUSIONS This study demonstrates the preclinical efficacy of a novel soluble ACE2 protein, termed ACE2-1-618-DDC-ABD, in a lethal mouse model of SARS-CoV-2 infection that develops severe lung injury and variable degrees of moderate kidney proximal tubular injury.
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Affiliation(s)
- Luise Hassler
- Division of Nephrology/Hypertension, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
| | - Jan Wysocki
- Division of Nephrology/Hypertension, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
| | - Ian Gelarden
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
| | - Isha Sharma
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
| | - Anastasia Tomatsidou
- Department of Microbiology, The University of Chicago, Chicago, Illinois
- Ricketts Regional Biocontainment Laboratory, University of Chicago, Lemont, Illinois
| | - Minghao Ye
- Division of Nephrology/Hypertension, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
| | - Haley Gula
- Department of Microbiology, The University of Chicago, Chicago, Illinois
- Ricketts Regional Biocontainment Laboratory, University of Chicago, Lemont, Illinois
| | - Vlad Nicoleascu
- Department of Microbiology, The University of Chicago, Chicago, Illinois
- Ricketts Regional Biocontainment Laboratory, University of Chicago, Lemont, Illinois
| | - Glenn Randall
- Department of Microbiology, The University of Chicago, Chicago, Illinois
- Ricketts Regional Biocontainment Laboratory, University of Chicago, Lemont, Illinois
| | - Sergii Pshenychnyi
- Recombinant Protein Production Core, Northwestern University, Evanston, Illinois
| | - Nigar Khurram
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
| | - Yashpal Kanwar
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
| | - Dominique Missiakas
- Department of Microbiology, The University of Chicago, Chicago, Illinois
- Ricketts Regional Biocontainment Laboratory, University of Chicago, Lemont, Illinois
| | - Jack Henkin
- Center for Developmental Therapeutics, Northwestern University, Evanston, Illinois
| | - Anjana Yeldandi
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
| | - Daniel Batlle
- Division of Nephrology/Hypertension, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
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31
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Stress-induced cardiometabolic perturbations, increased oxidative stress and ACE/ACE2 imbalance are improved by endurance training in rats. Life Sci 2022; 305:120758. [DOI: 10.1016/j.lfs.2022.120758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/26/2022] [Accepted: 06/27/2022] [Indexed: 11/22/2022]
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32
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Haidar MA, Shakkour Z, Reslan MA, Al-Haj N, Chamoun P, Habashy K, Kaafarani H, Shahjouei S, Farran SH, Shaito A, Saba ES, Badran B, Sabra M, Kobeissy F, Bizri M. SARS-CoV-2 involvement in central nervous system tissue damage. Neural Regen Res 2022; 17:1228-1239. [PMID: 34782556 PMCID: PMC8643043 DOI: 10.4103/1673-5374.327323] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 06/30/2021] [Accepted: 07/28/2021] [Indexed: 12/18/2022] Open
Abstract
As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread globally, it became evident that the SARS-CoV-2 virus infects multiple organs including the brain. Several clinical studies revealed that patients with COVID-19 infection experience an array of neurological signs ranging in severity from headaches to life-threatening strokes. Although the exact mechanism by which the SARS-CoV-2 virus directly impacts the brain is not fully understood, several theories have been suggested including direct and indirect pathways induced by the virus. One possible theory is the invasion of SARS-CoV-2 to the brain occurs either through the bloodstream or via the nerve endings which is considered to be the direct route. Such findings are based on studies reporting the presence of viral material in the cerebrospinal fluid and brain cells. Nevertheless, the indirect mechanisms, including blood-clotting abnormalities and prolonged activation of the immune system, can result in further tissue and organ damages seen during the course of the disease. This overview attempts to give a thorough insight into SARS-CoV-2 coronavirus neurological infection and highlights the possible mechanisms leading to the neurological manifestations observed in infected patients.
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Affiliation(s)
- Muhammad Ali Haidar
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Zaynab Shakkour
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Mohammad Amine Reslan
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Nadine Al-Haj
- Faculty of Health Sciences, University of Balamand, Beirut, Lebanon
| | - Perla Chamoun
- Faculty of Medicine, University of Balamand, Koura, Lebanon
| | - Karl Habashy
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | | | - Shima Shahjouei
- Program for Neurotrauma, Neuroproteomics & Biomarkers Research, Departments of Emergency Medicine, University of Florida, Gainesville, FL, USA
| | - Sarah H. Farran
- Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | | | - Esber S. Saba
- Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Bassam Badran
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Beirut, Lebanon
| | - Mirna Sabra
- Faculty of Medicine, Lebanese University, Neuroscience Research Center (NRC), Beirut, Lebanon
| | - Firas Kobeissy
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Neuroscience Institute, Neurology Department, Geisinger Health System, PA, USA
| | - Maya Bizri
- Department of Psychiatry, American University of Beirut, Beirut, Lebanon
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33
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Dörr K, Kammer M, Reindl-Schwaighofer R, Lorenz M, Marculescu R, Poglitsch M, Beitzke D, Oberbauer R. The Effect of FGF23 on Cardiac Hypertrophy Is Not Mediated by Systemic Renin-Angiotensin- Aldosterone System in Hemodialysis. Front Med (Lausanne) 2022; 9:878730. [PMID: 35559350 PMCID: PMC9086596 DOI: 10.3389/fmed.2022.878730] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 04/05/2022] [Indexed: 01/08/2023] Open
Abstract
Fibroblast growth factor 23 (FGF23) is elevated in patients with chronic kidney disease and contributes to left ventricular hypertrophy (LVH). The aim of the analysis was to determine whether this effect is mediated by the renin-angiotensin-aldosterone system (RAAS) in hemodialysis. Serum samples from 62 randomized hemodialysis patients with LVH were analyzed for plasma renin activity (PRA-S), angiotensin II (AngII), and metabolites, angiotensin-converting enzyme-2 (ACE2) and aldosterone using a high throughput mass spectrometry assay. Compared to healthy individuals, levels of the RAAS parameters PRA-S, AngII and aldosterone were generally lower [median (IQR) PRA-S 130 (46–269) vs. 196 (98, 238) pmol/L; AngII 70 (28–157) vs. 137 (76, 201) pmol/L; Aldosterone 130 (54, 278) vs. 196 (98, 238) pmol/L]. We did not find an indication that the effect of FGF23 on LVH was mediated by RAAS parameters, with all estimated indirect effects virtually zero. Furthermore, FGF23 was not associated with RAAS parameter levels throughout the study. While there was a clear association between FGF23 levels and left ventricular mass index (LVMI) at the end of the study and in the FGF23 fold change and LVMI change analysis, no association between RAAS and LVMI was observed. Serum concentrations of PRA-S, AngII, and aldosterone were below the ranges measured in healthy controls suggesting that RAAS is not systemically activated in hemodialysis patients. The effect of FGF23 on LVMI was not mediated by systemic RAAS activity. These findings challenge the current paradigm of LVH progression and treatment with RAAS blockers in dialysis.
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Affiliation(s)
- Katharina Dörr
- Department of Nephrology, Medical University of Vienna, Vienna, Austria
| | - Michael Kammer
- Department of Nephrology, Medical University of Vienna, Vienna, Austria.,Center for Medical Statistics, Informatics, and Intelligent Systems, Section for Clinical Biometrics, Medical University of Vienna, Vienna, Austria
| | | | | | - Rodrig Marculescu
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | | | - Dietrich Beitzke
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Cardiovascular and Interventional Radiology, Medical University of Vienna, Vienna, Austria
| | - Rainer Oberbauer
- Department of Nephrology, Medical University of Vienna, Vienna, Austria
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34
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Kalejaiye TD, Bhattacharya R, Burt MA, Travieso T, Okafor AE, Mou X, Blasi M, Musah S. SARS-CoV-2 Employ BSG/CD147 and ACE2 Receptors to Directly Infect Human Induced Pluripotent Stem Cell-Derived Kidney Podocytes. Front Cell Dev Biol 2022; 10:855340. [PMID: 35517495 PMCID: PMC9065256 DOI: 10.3389/fcell.2022.855340] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 03/18/2022] [Indexed: 12/15/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the Coronavirus disease 2019 (COVID-19), which has resulted in over 5.9 million deaths worldwide. While cells in the respiratory system are the initial target of SARS-CoV-2, there is mounting evidence that COVID-19 is a multi-organ disease. Still, the direct affinity of SARS-CoV-2 for cells in other organs such as the kidneys, which are often targeted in severe COVID-19, remains poorly understood. We employed a human induced pluripotent stem (iPS) cell-derived model to investigate the affinity of SARS-CoV-2 for kidney glomerular podocytes, and examined the expression of host factors for binding and processing of the virus. We studied cellular uptake of the live SARS-CoV-2 virus as well as a pseudotyped virus. Infection of podocytes with live SARS-CoV-2 or spike-pseudotyped lentiviral particles revealed cellular uptake even at low multiplicity of infection (MOI) of 0.01. We found that direct infection of human iPS cell-derived podocytes by SARS-CoV-2 virus can cause cell death and podocyte foot process retraction, a hallmark of podocytopathies and progressive glomerular diseases including collapsing glomerulopathy observed in patients with severe COVID-19 disease. We identified BSG/CD147 and ACE2 receptors as key mediators of spike binding activity in human iPS cell-derived podocytes. These results show that SARS-CoV-2 can infect kidney glomerular podocytes in vitro via multiple binding interactions and partners, which may underlie the high affinity of SARS-CoV-2 for kidney tissues. This stem cell-derived model is potentially useful for kidney-specific antiviral drug screening and mechanistic studies of COVID-19 organotropism.
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Affiliation(s)
- Titilola D. Kalejaiye
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, United States
| | - Rohan Bhattacharya
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, United States
- Center for Biomolecular and Tissue Engineering, Duke University, Durham, NC, United States
| | - Morgan A. Burt
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, United States
| | - Tatianna Travieso
- Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, United States
- Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, United States
| | - Arinze E. Okafor
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, United States
| | - Xingrui Mou
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, United States
| | - Maria Blasi
- Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, United States
- Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, United States
| | - Samira Musah
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, United States
- Center for Biomolecular and Tissue Engineering, Duke University, Durham, NC, United States
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, United States
- Developmental and Stem Cell Biology Program, Duke University, Durham, NC, United States
- Department of Cell Biology, Duke University, Durham, NC, United States
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Xie X, Li J, Liu P, Wang M, Gao L, Wan F, Lv J, Zhang H, Jin J. Chimeric Fusion between Clostridium ramosum IgA Protease and IgG Fc Provides Long-lasting Clearance of IgA deposits in Mouse Models of IgA Nephropathy. J Am Soc Nephrol 2022; 33:918-935. [PMID: 35172987 PMCID: PMC9063903 DOI: 10.1681/asn.2021030372] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 01/25/2022] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND IgA nephropathy is a common primary glomerulonephritis caused by mesangial deposition of poly-IgA complexes. The disease follows a variable course of clinical progression with a high risk of kidney failure. While no specific therapy is available, enzymatic strategies to clear IgA deposits are being considered for the treatment of rapidly progressive IgA nephropathy. METHODS We chose an IgA protease of commensal bacterium Clostridium ramosum, termed AK183, as the template for constructing a recombinant biologic. To extend the half-life in blood, we fused AK183 to the Fc segment of human IgG1. Activities of this Fc-AK183 fusion protein towards the cleavage and subsequent clearance of IgA were tested in mouse models. RESULTS First, we discovered an autocleavage activity of AK183 that separates the N-terminal protease from its C-terminal autotransporter β domain. Therefore, we grafted Fc to the N-terminus of AK183 and demonstrated its week-long enzymatic activity in mice. In addition, the proteolytic fragments of IgA generated in the reaction with Fc-AK183 were effectively removed from circulation via kidney filtration. The combined actions of Fc-AK183-mediated cleavage and subsequent renal clearance of IgA resulted in a lasting obliteration of blood IgA, as demonstrated in a human IgA-injection model and in a humanized α1KI transgenic model. Fc-AK183 was also able to remove chronic IgA and associated complement C3 deposits in the glomerulus. CONCLUSION We constructed a chimeric fusion of IgA protease with Fc and demonstrated its long-lasting efficacy as a promising targeted therapy for IgA nephropathy.
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Affiliation(s)
- Xinfang Xie
- X Xie, Department of Medicine-Nephrology and Hypertension, Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, United States
| | - Jingyi Li
- J Li, Renal Division, Peking University First Hospital, Beijing, China
| | - Pan Liu
- P Liu, Department of Medicine-Nephrology and Hypertension, Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, United States
| | - Manliu Wang
- M Wang, Renal Division, Peking University First Hospital, Beijing, China
| | - Li Gao
- L Gao, Department of Medicine-Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, United States
| | - Feng Wan
- F Wan, Renal Division, Peking University First Hospital, Beijing, China
| | - Jicheng Lv
- J Lv, Renal Division, Peking University First Hospital, Beijing, China
| | - Hong Zhang
- H Zhang, Renal Division, Peking University First Hospital, Beijing, China
| | - Jing Jin
- J Jin, Department of Medicine-Nephrology and Hypertension, Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, United States
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An Adverse Outcomes Approach to Study the Effects of SARS-CoV-2 in 3D Organoid Models. J Mol Biol 2022; 434:167213. [PMID: 34437890 PMCID: PMC8381630 DOI: 10.1016/j.jmb.2021.167213] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 08/16/2021] [Accepted: 08/17/2021] [Indexed: 02/07/2023]
Abstract
The novel SARS-CoV-2 virus outbreak is the major cause of a respiratory disease known as COVID-19. It has caused a global pandemic and has resulted in mortality in millions. The primary mode of infection is respiratory ailments, however, due to multi-organ complications, COVID-19 patients displays a greater mortality numbers. Due to the 3Rs Principle (Refine, Reduce, Replacement), the scientific community has shifted its focus to 3D organoid models rather than testing animal models. 3D organoid models provide a better physiological architecture as it mimics the real tissue microenvironment and is the best platform to recapitulate organs in a dish. Hence, the organoid approach provides a more realistic drug response in comparison to the traditional 2D cellular models, which lack key physiological relevance due to the absence of proper surface topography and cellular interactions. Furthermore, an adverse outcome pathway (AOPs) provides a best fit model to identify various molecular and cellular events during the exposure of SARS-CoV-2. Hence, 3D organoid research provides information related to gene expression, cell behavior, antiviral studies and ACE2 expression in various organs. In this review, we discuss state-of-the-art lung, liver and kidney 3D organoid system utilizing the AOPs to study SARS-CoV-2 molecular pathogenesis. Furthermore, current challenges are discussed for future application of 3D organoid systems for various disease states.
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Tzotzos S. Stapled peptides as potential inhibitors of SARS‐CoV‐2 binding to the hACE2 receptor. J Pept Sci 2022; 28:e3409. [PMID: 35165970 PMCID: PMC9111031 DOI: 10.1002/psc.3409] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 02/10/2022] [Accepted: 02/10/2022] [Indexed: 12/03/2022]
Abstract
Stapled peptides are synthetic peptidomimetics of bioactive sites in folded proteins which carry chemical links, introduced during peptide synthesis, designed to retain the secondary structure in the native protein molecule. Stapled peptides have been investigated as potential modulators of protein–protein interactions for over two decades. The potential use of stapled peptides as inhibitors of viral entry, and therefore as antiviral therapeutics, has been established for several important viruses causing disease in humans, such as the human immunodeficiency virus type 1 (HIV‐1), respiratory syncytial virus (RSV), and Middle East Respiratory Syndrome (MERS) coronavirus. Several independent research initiatives have investigated the inhibitory effect of stapled peptides on binding of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the causative agent of COVID‐19, to its receptor, angiotensin‐converting‐enzyme 2 (ACE2). These stapled peptides, which mimic Helix 1 of the human ACE2 receptor, have demonstrated mixed ability to prevent infection with SARS‐CoV‐2 in cell‐based studies.
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38
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Mitochondrial Pathophysiology on Chronic Kidney Disease. Int J Mol Sci 2022; 23:ijms23031776. [PMID: 35163697 PMCID: PMC8836100 DOI: 10.3390/ijms23031776] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/01/2022] [Accepted: 02/02/2022] [Indexed: 02/04/2023] Open
Abstract
In healthy kidneys, interstitial fibroblasts are responsible for the maintenance of renal architecture. Progressive interstitial fibrosis is thought to be a common pathway for chronic kidney diseases (CKD). Diabetes is one of the boosters of CKD. There is no effective treatment to improve kidney function in CKD patients. The kidney is a highly demanding organ, rich in redox reactions occurring in mitochondria, making it particularly vulnerable to oxidative stress (OS). A dysregulation in OS leads to an impairment of the Electron transport chain (ETC). Gene deficiencies in the ETC are closely related to the development of kidney disease, providing evidence that mitochondria integrity is a key player in the early detection of CKD. The development of novel CKD therapies is needed since current methods of treatment are ineffective. Antioxidant targeted therapies and metabolic approaches revealed promising results to delay the progression of some markers associated with kidney disease. Herein, we discuss the role and possible origin of fibroblasts and the possible potentiators of CKD. We will focus on the important features of mitochondria in renal cell function and discuss their role in kidney disease progression. We also discuss the potential of antioxidants and pharmacologic agents to delay kidney disease progression.
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Nomura H, Kuruppu S, Rajapakse NW. Stimulation of Angiotensin Converting Enzyme 2: A Novel Treatment Strategy for Diabetic Nephropathy. Front Physiol 2022; 12:813012. [PMID: 35087423 PMCID: PMC8787214 DOI: 10.3389/fphys.2021.813012] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 12/20/2021] [Indexed: 12/11/2022] Open
Abstract
Despite current therapies for diabetic nephropathy, many patients continue to progress to end-stage renal disease requiring renal replacement therapy. While the precise mechanisms underlying diabetic nephropathy remain to be determined, it is well established that chronic activation of the renin angiotensin aldosterone system (RAAS) plays a substantial role in the pathogenesis of diabetic nephropathy. Angiotensin converting enzyme 2 (ACE2), the enzyme responsible for activating the reno-protective arm of the RAAS converts angiotensin (Ang) II into Ang 1-7 which exerts reno-protective effects. Chronic RAAS activation leads to kidney inflammation and fibrosis, and ultimately lead to end-stage kidney disease. Currently, angiotensin converting enzyme inhibitors and Ang II receptor blockers are approved for renal fibrosis and inflammation. Targeting the reno-protective arm of the RAAS should therefore, provide further treatment options for kidney fibrosis and inflammation. In this review, we examine how targeting the reno-protective arm of the RAAS can ameliorate kidney inflammation and fibrosis and rescue kidney function in diabetic nephropathy. We argue tissue ACE2 stimulation provides a unique and promising therapeutic approach for diabetic nephropathy.
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Affiliation(s)
- Haru Nomura
- School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia
| | - Sanjaya Kuruppu
- Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - Niwanthi W Rajapakse
- School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia
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40
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Kushkestani M, Parvani M, Kazemzadeh Y. SARS-COV-2 in Type 2 Diabetic Patients: Possible Roles of Exercise Training as a Medicine. Curr Diabetes Rev 2022; 18:e010921196029. [PMID: 34468301 DOI: 10.2174/1573399817666210901121824] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/22/2021] [Accepted: 06/24/2021] [Indexed: 01/08/2023]
Abstract
SARS-COV-2 is the novel type of beta coronavirus that was first evolved in December 2019 in Wuhan, China. People with type 2 diabetes are the most vulnerable group to SARS-COV-2 and its associated complications. Many factors such as medication, pathophysiologic-induced compensatory mechanisms, and alterations in protein expression and immune system function can all contribute to severe outcomes in diabetics. In this review article, we first described the possible mechanisms of increased risk and more severe complications rate of SARS-COV-2 in diabetic patients. Secondly, we discussed the crucial role of exercise in diabetic patients in balancing the RAS system (ACE2/ACE). Finally, we examine the possible roles of acute and chronic exercise in reducing SARS-COV-2 severe outcomes in people with diabetes in accordance with the latest evidence. We concluded that regular exercise (especially moderate-intensity exercise) can play a role in immune- enhancing, anti-inflammatory, and anti-oxidant activities and can balance the ACE2/ACE ratio (decreasing ANG2 levels) in diabetic subjects.
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Affiliation(s)
- Mehdi Kushkestani
- Faculty of Physical Education and Sport Sciences, Allameh Tabataba\'i University, Tehran, Iran
| | - Mohsen Parvani
- Faculty of Physical Education and Sport Sciences, Allameh Tabataba\'i University, Tehran, Iran
| | - Yaser Kazemzadeh
- Department of Physiology Islamshahr Branch, Islamic Azad University, Islamshahr, Iran
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Amezcua-Guerra LM, Del Valle L, González-Pacheco H, Springall R, Márquez-Velasco R, Massó F, Brianza-Padilla M, Manzur-Sandoval D, González-Flores J, García-Ávila C, Juárez-Vicuña Y, Sánchez-Muñoz F, Ballinas-Verdugo MA, Basilio-Gálvez E, Paez-Arenas A, Castillo-Salazar M, Cásares-Alvarado S, Hernández-Diazcouder A, Sánchez-Gloria JL, Tavera-Alonso C, Gopar-Nieto R, Sandoval J. The prognostic importance of the angiotensin II/angiotensin-(1-7) ratio in patients with SARS-CoV-2 infection. Ther Adv Respir Dis 2022; 16:17534666221122544. [PMID: 36082632 PMCID: PMC9465579 DOI: 10.1177/17534666221122544] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Background: Information about angiotensin II (Ang II), angiotensin-converting enzyme 2
(ACE2), and Ang-(1–7) levels in patients with COVID-19 is scarce. Objective: To characterize the Ang II–ACE2–Ang-(1–7) axis in patients with SARS-CoV-2
infection to understand its role in pathogenesis and prognosis. Methods: Patients greater than 18 years diagnosed with COVID-19, based on clinical
findings and positive RT-PCR test, who required hospitalization and
treatment were included. We compared Ang II, aldosterone, Ang-(1–7), and
Ang-(1–9) concentrations and ACE2 concentration and activity between
COVID-19 patients and historic controls. We compared baseline demographics,
laboratory results (enzyme, peptide, and inflammatory marker levels), and
outcome (patients who survived versus those who died). Results: Serum from 74 patients [age: 58 (48–67.2) years; 68% men] with moderate (20%)
or severe (80%) COVID-19 were analyzed. During 13 (10–21) days of
hospitalization, 25 patients died from COVID-19 and 49 patients survived.
Compared with controls, Ang II concentration was higher and Ang-(1–7)
concentration was lower, despite significantly higher ACE2 activity in
patients. Ang II concentration was higher and Ang-(1–7) concentration was
lower in patients who died. The Ang II/Ang-(1–7) ratio was significantly
higher in patients who died. In multivariate analysis, Ang II/Ang-(1–7)
ratio greater than 3.45 (OR = 5.87) and lymphocyte count
⩽0.65 × 103/µl (OR = 8.43) were independent predictors of
mortality from COVID-19. Conclusion: In patients with severe SARS-CoV-2 infection, imbalance in the Ang
II–ACE2–Ang-(1–7) axis may reflect deleterious effects of Ang II and may
indicate a worse outcome.
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Affiliation(s)
- Luis M Amezcua-Guerra
- Immunology Department, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | - Leonardo Del Valle
- Pharmacology Department, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | | | - Rashidi Springall
- Immunology Department, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | | | - Felipe Massó
- Translational Medicine Lab UNAM-INC Unit, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | | | - Daniel Manzur-Sandoval
- Intensive Care Unit, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | | | - Carlos García-Ávila
- Immunology Department, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | - Yaneli Juárez-Vicuña
- Immunology Department, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | - Fausto Sánchez-Muñoz
- Immunology Department, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | | | - Edna Basilio-Gálvez
- Immunology Department, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | - Araceli Paez-Arenas
- Translational Medicine Lab UNAM-INC Unit, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | | | | | | | - José L Sánchez-Gloria
- Immunology Department, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | | | - Rodrigo Gopar-Nieto
- Coronary Care Unit, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | - Julio Sandoval
- Immunology Department, Ignacio Chávez National Institute of Cardiology, Juan Badiano # 1, Colonia Sección XVI Tlalpan, México City 14080, México
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Drug repurposing for SARS-CoV-2 (COVID-19) treatment. CORONAVIRUS DRUG DISCOVERY 2022. [PMCID: PMC9217734 DOI: 10.1016/b978-0-323-85156-5.00027-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Drug repurposing involves the process of investigating already existing drugs with an aim to use them for different therapeutic purposes than the intended one. This approach is relatively faster, less costly, and reliable in terms of safety as the drug under study is already derisked and known for its other chemistry and pharmacokinetic properties. With these benefits in mind, it is a very reliable way to undertake drug development for emerging diseases such as COVID-19 which demand immediate interventions to slow or completely stop its havoc on mankind. One of the biggest challenges that drug repurposing has is the possibility of the occurrence of new mechanisms of action between the drug ligand and some proteins in the human physiology. Drug repurposing appears to have settled in the meantime in drug development, though more studies in the future will be warranted particularly in regards to resistance.
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Pagliaro P, Thairi C, Alloatti G, Penna C. Angiotensin-converting enzyme 2: a key enzyme in key organs. J Cardiovasc Med (Hagerstown) 2022; 23:1-11. [PMID: 34091532 DOI: 10.2459/jcm.0000000000001218] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
2020 marked the 20th anniversary of the discovery of the angiotensin-converting enzyme 2 (ACE2). This major event that changed the way we see the renin-angiotensin system today could have passed quietly. Instead, the discovery that ACE2 is a major player in the severe acute respiratory syndrome coronavirus 2 pandemic has blown up the literature regarding this enzyme. ACE2 connects the classical arm renin-angiotensin system, consisting mainly of angiotensin II peptide and its AT1 receptor, with a protective arm, consisting mainly of the angiotensin 1-7 peptide and its Mas receptor. In this brief article, we have reviewed the literature to describe how ACE2 is a key protective arm enzyme in the function of many organs, particularly in the context of brain and cardiovascular function, as well as in renal, pulmonary and digestive homeostasis. We also very briefly review and refer to recent literature to present an insight into the role of ACE2 in determining the course of coronavirus diseases 2019.
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Affiliation(s)
- Pasquale Pagliaro
- Department of Clinical and Biological Sciences, University of Turin, Turin
| | - Cecilia Thairi
- Department of Clinical and Biological Sciences, University of Turin, Turin
| | | | - Claudia Penna
- Department of Clinical and Biological Sciences, University of Turin, Turin
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Oliveira LCG, Cruz NAN, Ricelli B, Tedesco-Silva H, Medina-Pestana JO, Casarini DE. Interactions amongst inflammation, renin-angiotensin-aldosterone and kallikrein-kinin systems: suggestive approaches for COVID-19 therapy. J Venom Anim Toxins Incl Trop Dis 2021; 27:e20200181. [PMID: 34925477 PMCID: PMC8651214 DOI: 10.1590/1678-9199-jvatitd-2020-0181] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 03/24/2021] [Indexed: 01/08/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is a rapid-spread infectious disease caused by the SARS-CoV-2 virus, which can culminate in the renin-angiotensin-aldosterone (RAAS) and kallikrein-kinin (KKS) systems imbalance, and in serious consequences for infected patients. This scoping review of published research exploring the RAAS and KKS was undertaken in order to trace the history of the discovery of both systems and their multiple interactions, discuss some aspects of the viral-cell interaction, including inflammation and the system imbalance triggered by SARS-CoV-2 infection, and their consequent disorders. Furthermore, we correlate the effects of continued use of the RAAS blockers in chronic diseases therapies with the virulence and physiopathology of COVID-19. We also approach the RAAS and KKS-related proposed potential therapies for treatment of COVID-19. In this way, we reinforce the importance of exploring both systems and the application of their components or their blockers in the treatment of coronavirus disease.
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Affiliation(s)
| | | | - Bruna Ricelli
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, SP, Brazil
| | - Helio Tedesco-Silva
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, SP, Brazil
| | - José Osmar Medina-Pestana
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, SP, Brazil
| | - Dulce Elena Casarini
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, SP, Brazil
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Ma LL, Liu HM, Liu XM, Yuan XY, Xu C, Wang F, Lin JZ, Xu RC, Zhang DK. Screening S protein - ACE2 blockers from natural products: Strategies and advances in the discovery of potential inhibitors of COVID-19. Eur J Med Chem 2021; 226:113857. [PMID: 34628234 PMCID: PMC8489279 DOI: 10.1016/j.ejmech.2021.113857] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/11/2021] [Accepted: 09/15/2021] [Indexed: 02/09/2023]
Abstract
The Coronavirus disease, 2019 (COVID-19) is caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), which poses a major threat to human life and health. Given its continued development, limiting the spread of COVID-19 in the population remains a challenging task. Currently, multiple therapies are being tried around the world to deal with SARS-CoV-2 infection, and a variety of studies have shown that natural products have a significant effect on COVID-19 patients. The combination of SARS-CoV-2 S protein with Angiotensin converting enzyme II(ACE2) of host cell to promote membrane fusion is an initial critical step for SARS-CoV-2 infection. Therefore, screening natural products that inhibit the binding of SARS-CoV-2 S protein and ACE2 also provides a feasible strategy for the treatment of COVID-19. Establishment of high throughput screening model is an important basis and key technology for screening S protein-ACE2 blockers. Based on this, the molecular structures of SARS-CoV-2 and ACE2 and their processes in the life cycle of SARS-CoV-2 and host cell infection were firstly reviewed in this paper, with emphasis on the methods and techniques of screening S protein-ACE2 blockers, including Virtual Screening (VS), Surface Plasmon Resonance (SPR), Biochromatography, Biotin-avidin with Enzyme-linked Immunosorbent assay and Gene Chip Technology. Furthermore, the technical principle, advantages and disadvantages and application scope were further elaborated. Combined with the application of the above screening technologies in S protein-ACE2 blockers, a variety of natural products, such as flavonoids, terpenoids, phenols, alkaloids, were summarized, which could be used as S protein-ACE2 blockers, in order to provide ideas for the efficient discovery of S protein-ACE2 blockers from natural sources and contribute to the development of broad-spectrum anti coronavirus drugs.
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Affiliation(s)
- Le-le Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Hui-Min Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Xue-Mei Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Xiao-Yu Yuan
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Chao Xu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Fang Wang
- Key Laboratory of Modern Chinese Medicine Preparation of Ministry of Education, Jiangxi University of Traditional Chinese Medicine Central Laboratory, Nanchang, 330000, PR China
| | - Jun-Zhi Lin
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, PR China.
| | - Run-Chun Xu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China.
| | - Ding-Kun Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China.
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Tran S, Kuruppu S, Rajapakse NW. Chronic Renin-Angiotensin System Activation Induced Neuroinflammation: Common Mechanisms Underlying Hypertension and Dementia? J Alzheimers Dis 2021; 85:943-955. [PMID: 34897090 DOI: 10.3233/jad-215231] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Hypertension is a major risk factor for the pathogenesis of vascular dementia and Alzheimer's disease. Chronic activation of the renin-angiotensin system (RAS) contributes substantially to neuroinflammation. We propose that neuroinflammation arising from chronic RAS activation can initiate and potentiate the onset of hypertension and related dementia. Neuroinflammation induced by chronic activation of the RAS plays a key role in the pathogenesis of dementia. Increased levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and transforming growth factor (TGF)-β have been reported in brain tissue of vascular dementia patients and animal models of vascular dementia induced by either angiotensin II infusion or transverse aortic coarctation. It is proposed that neuronal cell death and synaptic dysfunction induced by neuroinflammation lead to cognitive impairment in dementia. The neuroprotective RAS pathway, regulated by angiotensin-converting enzyme 2 (ACE2) which converts angiotensin II into angiotensin-(1-7), can attenuate hypertension and dementia. Furthermore, the use of anti-hypertensive medications in preventing dementia or cognitive decline in hypertensive patients and animal models of dementia have mostly been beneficial. Current evidence suggests a strong link between RAS induced neuroinflammation and the onset of hypertension and dementia, which warrants further investigation. Strategies to counteract an overactive RAS and enhance the neuroprotective arm of the RAS may help prevent or improve cognitive impairment associated with hypertension.
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Affiliation(s)
- Shirley Tran
- School of Biomedical Sciences, University of Queensland, St. Lucia, QLD, Australia
| | - Sanjaya Kuruppu
- School of Biomedical Sciences, University of Queensland, St. Lucia, QLD, Australia.,Department of Biochemistry & Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Niwanthi W Rajapakse
- School of Biomedical Sciences, University of Queensland, St. Lucia, QLD, Australia
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Xie F, Su P, Pan T, Zhou X, Li H, Huang H, Wang A, Wang F, Huang J, Yan H, Zeng L, Zhang L, Zhou F. Engineering Extracellular Vesicles Enriched with Palmitoylated ACE2 as COVID-19 Therapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2021; 33:e2103471. [PMID: 34665481 PMCID: PMC8646473 DOI: 10.1002/adma.202103471] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 08/21/2021] [Indexed: 05/22/2023]
Abstract
Angiotensin converting enzyme 2 (ACE2) is a key receptor present on cell surfaces that directly interacts with the viral spike (S) protein of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). It is proposed that inhibiting this interaction can be promising in treating COVID-19. Here, the presence of ACE2 in extracellular vesicles (EVs) is reported and the EV-ACE2 levels are determined by protein palmitoylation. The Cys141 and Cys498 residues on ACE2 are S-palmitoylated by zinc finger DHHC-Type Palmitoyltransferase 3 (ZDHHC3) and de-palmitoylated by acyl protein thioesterase 1 (LYPLA1), which is critical for the membrane-targeting of ACE2 and their EV secretion. Importantly, by fusing the S-palmitoylation-dependent plasma membrane (PM) targeting sequence with ACE2, EVs enriched with ACE2 on their surface (referred to as PM-ACE2-EVs) are engineered. It is shown that PM-ACE2-EVs can bind to the SARS-CoV-2 S-RBD with high affinity and block its interaction with cell surface ACE2 in vitro. PM-ACE2-EVs show neutralization potency against pseudotyped and authentic SARS-CoV-2 in human ACE2 (hACE2) transgenic mice, efficiently block viral load of authentic SARS-CoV-2, and thus protect host against SARS-CoV-2-induced lung inflammation. The study provides an efficient engineering protocol for constructing a promising, novel biomaterial for application in prophylactic and therapeutic treatments against COVID-19.
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Affiliation(s)
- Feng Xie
- School of MedicineZhejiang University City CollegeHangzhou310015China
- Institutes of Biology and Medical ScienceSoochow UniversitySuzhou215123China
| | - Peng Su
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Ting Pan
- Center for Infection and Immunity StudiesSchool of MedicineSun Yat‐sen UniversityShenzhen518107China
| | - Xiaoxue Zhou
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Heyu Li
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Huizhe Huang
- Faculty of Basic Medical SciencesChongqing Medical UniversityMedical College Road 1Chongqing400016China
| | - Aijun Wang
- Department of SurgerySchool of MedicineUC DavisDavisCA95817USA
| | - Fangwei Wang
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Jun Huang
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Haiyan Yan
- School of MedicineZhejiang University City CollegeHangzhou310015China
| | - Linghui Zeng
- School of MedicineZhejiang University City CollegeHangzhou310015China
| | - Long Zhang
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Fangfang Zhou
- Institutes of Biology and Medical ScienceSoochow UniversitySuzhou215123China
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Rajtik T, Galis P, Bartosova L, Paulis L, Goncalvesova E, Klimas J. Alternative RAS in Various Hypoxic Conditions: From Myocardial Infarction to COVID-19. Int J Mol Sci 2021; 22:ijms222312800. [PMID: 34884604 PMCID: PMC8657827 DOI: 10.3390/ijms222312800] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 11/20/2021] [Accepted: 11/24/2021] [Indexed: 12/28/2022] Open
Abstract
Alternative branches of the classical renin–angiotensin–aldosterone system (RAS) represent an important cascade in which angiotensin 2 (AngII) undergoes cleavage via the action of the angiotensin-converting enzyme 2 (ACE2) with subsequent production of Ang(1-7) and other related metabolites eliciting its effects via Mas receptor activation. Generally, this branch of the RAS system is described as its non-canonical alternative arm with counterbalancing actions to the classical RAS, conveying vasodilation, anti-inflammatory, anti-remodeling and anti-proliferative effects. The implication of this branch was proposed for many different diseases, ranging from acute cardiovascular conditions, through chronic respiratory diseases to cancer, nonetheless, hypoxia is one of the most prominent common factors discussed in conjugation with the changes in the activity of alternative RAS branches. The aim of this review is to bring complex insights into the mechanisms behind the various forms of hypoxic insults on the activity of alternative RAS branches based on the different duration of stimuli and causes (acute vs. intermittent vs. chronic), localization and tissue (heart vs. vessels vs. lungs) and clinical relevance of studied phenomenon (experimental vs. clinical condition). Moreover, we provide novel insights into the future strategies utilizing the alternative RAS as a diagnostic tool as well as a promising pharmacological target in serious hypoxia-associated cardiovascular and cardiopulmonary diseases.
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Affiliation(s)
- Tomas Rajtik
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia; (P.G.); (L.B.); (J.K.)
- Correspondence: ; Tel.: +42-12-501-17-391
| | - Peter Galis
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia; (P.G.); (L.B.); (J.K.)
| | - Linda Bartosova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia; (P.G.); (L.B.); (J.K.)
| | - Ludovit Paulis
- Institute of Pathophysiology, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
| | - Eva Goncalvesova
- Department of Heart Failure, Clinic of Cardiology, National Institute of Cardiovascular Diseases, 831 01 Bratislava, Slovakia;
| | - Jan Klimas
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia; (P.G.); (L.B.); (J.K.)
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Kalejaiye TD, Bhattacharya R, Burt MA, Travieso T, Okafor AE, Mou X, Blasi M, Musah S. BSG/CD147 and ACE2 receptors facilitate SARS-CoV-2 infection of human iPS cell-derived kidney podocytes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2021. [PMID: 34816259 DOI: 10.1101/2021.11.16.468893] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
BACKGROUND Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the Coronavirus disease 2019 (COVID-19), which was declared a pandemic by the World Health Organization (WHO) in March 2020. The disease has caused more than 5.1 million deaths worldwide. While cells in the respiratory system are frequently the initial target for SARS-CoV-2, clinical studies suggest that COVID-19 can become a multi-organ disease in the most severe cases. Still, the direct affinity of SARS-CoV-2 for cells in other organs such as the kidneys, which are often affected in severe COVID-19, remains poorly understood. METHOD In this study, we employed a human induced pluripotent stem (iPS) cell-derived model to investigate the affinity of SARS-CoV-2 for kidney glomerular podocytes. We studied uptake of the live SARS-CoV-2 virus as well as pseudotyped viral particles by human iPS cell derived podocytes using qPCR, western blot, and immunofluorescence. Global gene expression and qPCR analyses revealed that human iPS cell-derived podocytes express many host factor genes (including ACE2, BSG/CD147, PLS3, ACTR3, DOCK7, TMPRSS2, CTSL CD209, and CD33) associated with SARS-CoV-2 binding and viral processing. RESULT Infection of podocytes with live SARS-CoV-2 or spike-pseudotyped lentiviral particles revealed viral uptake by the cells at low Multiplicity of Infection (MOI of 0.01) as confirmed by RNA quantification and immunofluorescence studies. Our results also indicate that direct infection of human iPS cell-derived podocytes by SARS-CoV-2 virus can cause cell death and podocyte foot process retraction, a hallmark of podocytopathies and progressive glomerular diseases including collapsing glomerulopathy observed in patients with severe COVID-19 disease. Additionally, antibody blocking experiments identified BSG/CD147 and ACE2 receptors as key mediators of spike binding activity in human iPS cell-derived podocytes. CONCLUSION These results show that SARS-CoV-2 can infect kidney glomerular podocytes in vitro . These results also show that the uptake of SARS-CoV-2 by kidney podocytes occurs via multiple binding interactions and partners, which may underlie the high affinity of SARS-CoV-2 for kidney tissues. This stem cell-derived model is potentially useful for kidney-specific antiviral drug screening and mechanistic studies of COVID-19 organotropism. SIGNIFICANT STATEMENT Many patients with COVID19 disease exhibit multiorgan complications, suggesting that SARS-CoV-2 infection can extend beyond the respiratory system. Acute kidney injury is a common COVID-19 complication contributing to increased morbidity and mortality. Still, SARS-Cov-2 affinity for specialized kidney cells remain less clear. By leveraging our protocol for stem cell differentiation, we show that SARS-CoV-2 can directly infect kidney glomerular podocytes by using multiple Spike-binding proteins including ACE2 and BSG/CD147. Our results also indicate that infection by SARS-CoV-2 virus can cause podocyte cell death and foot process effacement, a hallmark of podocytopathies including collapsing glomerulopathy observed in patients with severe COVID-19 disease. This stem cell-derived model is potentially useful for kidney-specific antiviral drug screening and mechanistic studies of COVID-19 organotropism.
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Picomolar inhibition of SARS-CoV-2 variants of concern by an engineered ACE2-IgG4-Fc fusion protein. Antiviral Res 2021; 196:105197. [PMID: 34774603 PMCID: PMC8579703 DOI: 10.1016/j.antiviral.2021.105197] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/27/2021] [Accepted: 10/26/2021] [Indexed: 01/06/2023]
Abstract
SARS-CoV-2 enters host cells after binding through its spike glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor. Soluble ACE2 ectodomains bind and neutralize the virus, yet their short in vivo half-live limits their therapeutic use. This limitation can be overcome by fusing the fragment crystallizable (Fc) part of human immunoglobulin G (IgG) to the ACE2 ectodomain, but this bears the risk of Fc-receptor activation and antibody-dependent cellular cytotoxicity. Here, we describe optimized ACE2-IgG4-Fc fusion constructs that avoid Fc-receptor activation, preserve the desired ACE2 enzymatic activity and show promising pharmaceutical properties. The engineered ACE2-IgG4-Fc fusion proteins neutralize the original SARS-CoV, pandemic SARS-CoV-2 as well as the rapidly spreading SARS-CoV-2 alpha, beta and delta variants of concern. Importantly, these variants of concern are inhibited at picomolar concentrations proving that ACE2-IgG4 maintains - in contrast to therapeutic antibodies - its full antiviral potential. Thus, ACE2-IgG4-Fc fusion proteins are promising candidate anti-antivirals to combat the current and future pandemics.
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