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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 2025; 42:767-786. [PMID: 39495586 DOI: 10.1089/ars.2024.0637] [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] [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. 42, 767-786.
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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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Jiang Z, Zhai C, Tang G. Novel Antihypertensive Medications to Target the Renin-Angiotensin System: Mechanisms and Research. Rev Cardiovasc Med 2025; 26:27963. [PMID: 40351692 PMCID: PMC12059749 DOI: 10.31083/rcm27963] [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: 11/07/2024] [Revised: 12/30/2024] [Accepted: 02/10/2025] [Indexed: 05/14/2025] Open
Abstract
An estimated 1.28 billion individuals in the global population suffer from hypertension. Importantly, uncontrolled hypertension is strongly linked to various cardiovascular and cerebrovascular diseases. The role of the renin-angiotensin system (RAS) is widely acknowledged in the development and progression of hypertension. This system comprises angiotensinogen, the renin/(pro)renin/(pro)renin receptor (PRR) axis, the renin/angiotensin-converting enzyme/angiotensin (Ang) II/Ang II type I receptor (AT1R) axis, the renin/angiotensin-converting enzyme (ACE) 2/Ang (1-7)/Mas receptor (MasR) axis, the alamandine/Mas-related G protein-coupled D (MrgD) receptor axis, and the renin/ACE/Ang II/Ang II type II receptor (AT2R) axis. Additionally, brain Ang III plays a vital role in regulating central blood pressure. The current overview presents the latest research findings on the mechanisms through which novel anti-hypertensive medications target the RAS. These include zilebesiran (targeting angiotensinogen), PRO20 (targeting the renin/(pro)renin/PRR axis), sacubitril/valsartan (targeting the renin/ACE/Ang II/AT1R axis), GSK2586881, Ang (1-7) and AVE0991 (targeting the renin/ACE2/Ang (1-7)/MasR axis), alamandine (targeting the alamandine/MrgD receptor axis), C21 and β-Pro7-Ang III (targeting the renin/ACE/Ang II/AT2R axis), EC33, and firibastat and NI956 (targeting brain Ang III).
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Affiliation(s)
- Zhe Jiang
- Department of Cardiology, Jiaxing University Master Degree Cultivation Base, Zhejiang Chinese Medical University, 310053 Hangzhou, Zhejiang, China
| | - Changlin Zhai
- Department of Cardiology, The Affiliated Hospital of Jiaxing University, 314001 Jiaxing, Zhejiang, China
| | - Guanmin Tang
- Department of Cardiology, The Affiliated Hospital of Jiaxing University, 314001 Jiaxing, Zhejiang, China
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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] [Grants] [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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Truong LD, Trostel J, Roncal C, Cara-Fuentes G, Miyazaki M, Miyazaki-Anzai S, Andres-Hernando A, Sasai F, Lanaspa M, Johnson RJ, Garcia GE. Production of Acetylcholine by Podocytes and its Protection from Kidney Injury in GN. J Am Soc Nephrol 2025; 36:205-218. [PMID: 39302734 PMCID: PMC11801748 DOI: 10.1681/asn.0000000000000492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 09/02/2024] [Indexed: 09/22/2024] Open
Abstract
Key Points Our study demonstrated the sole enzyme responsible for acetylcholine production, choline acetyltransferase, was expressed in podocytes. Acetylcholine decreased glomerular injury in GN by reducing inflammation and protecting endothelium. Choline acetyltransferase/acetylcholine production was induced in podocytes with drugs already available. Background One of the most important factors modulating endothelial health is acetylcholine; and while it is associated as a cholinergic neurotransmitter, it is also expressed by non-neuronal cells. However, its role in the kidney, which does not receive cholinergic innervation, remains unknown. Methods To determine whether acetylcholine is produced in the kidney, we used choline acetyltransferase (ChAT) (BAC)–enhanced green fluorescent protein (ChAT mice) transgenic mice in which enhanced green fluorescent protein is expressed under the control of the endogenous ChAT transcriptional regulatory elements. We then investigated the role of acetylcholine in kidney disease by inducing antiglomerular basement membrane GN (anti-GBM GN) in ChAT transgenic mice. Results We demonstrate ChAT, the sole enzyme responsible for acetylcholine production, was expressed in glomerular podocytes and produced acetylcholine. We also show during anti-GBM GN in ChAT transgenic mice, ChAT expression was induced in the glomeruli, mainly in podocytes, and protects mice from kidney injury with marked reduction of glomerular proliferation/fibrinoid necrosis (by 71%), crescent formation (by 98%), and tubular injury (by 78%). By contrast, specific knockout of podocyte ChAT worsened the severity of the disease. The mechanism of protection included reduction of inflammation, attenuation of angiogenic factors reduction, and increase of endothelial nitric oxide synthase expression. In vitro and in vivo studies demonstrated available drugs such as cholinesterase inhibitors and ChAT inducers increased the expression of podocyte-ChAT and acetylcholine production. Conclusions These findings suggest de novo synthesis of acetylcholine by podocytes protected against inflammation and glomerular endothelium damage in anti-GBM GN. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_12_05_ASN0000000000000492.mp3
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Affiliation(s)
- Luan D. Truong
- Department of Pathology, Baylor College of Medicine, The Houston Methodist Hospital, Houston, Texas
| | - Jessica Trostel
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Carlos Roncal
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Gabriel Cara-Fuentes
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Makoto Miyazaki
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Shinobu Miyazaki-Anzai
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Ana Andres-Hernando
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Fumihiko Sasai
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Miguel Lanaspa
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Richard J. Johnson
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Gabriela E. Garcia
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
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Yskak A, Sokharev Y, Zhumalynov K, Koneva E, Afanasyeva N, Borodulin D, Babaskin D, Nugmanov A, Nurushev M, Chashkov V. Hormonal Implications of SARS-CoV-2: A Review of Endocrine Disruptions. SCIENTIFICA 2025; 2025:7305185. [PMID: 39830837 PMCID: PMC11742418 DOI: 10.1155/sci5/7305185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 04/27/2024] [Accepted: 11/22/2024] [Indexed: 01/22/2025]
Abstract
To improve medical care and rehabilitation algorithms for patients affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is important to evaluate and summarize the available data on the effect of coronavirus infection (COVID-19) on the endocrine system. The purpose of this review was to study the effect of COVID-19 on the endocrine system. The scientific novelty of this study is the evaluation of the effect of coronavirus infection on the endocrine system and the potential effect of hormones on susceptibility to COVID-19. The results of this review show that the endocrine system is vulnerable to disorders caused by COVID-19, mainly thyroid dysfunction and hyperglycemia. The information in the published literature mentioned here contains some unclear aspects and contradictory data, but much remains to be studied and clarified regarding the impact of COVID-19 on the endocrine system. In particular, this concerns the study of the hyperglycemic status of patients who have had coronavirus infection, which is extremely important for the future metabolic health of COVID-19 survivors. This review contributes to the scientific discourse by systematically synthesizing disparate studies to identify patterns, gaps, and emerging trends in the literature concerning the effects of COVID-19 on the endocrine system. By integrating these findings, this study offers a novel perspective on potential hormonal interactions influencing COVID-19 susceptibility and outcomes, proposing new hypotheses and frameworks for future research.
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Affiliation(s)
- Aliya Yskak
- Research Institute of Applied Biotechnology, Akhmet Baitursynuly Kostanay Regional University, Kostanay, Kazakhstan
- Faculty of Soil Science, Lomonosov Moscow State University, Moscow, Russia
| | - Yevgeniy Sokharev
- Pathological Anatomy Department, Municipal State Company “Kostanay Regional Pathoanatomical Bureau” of the Health Department of the Akimat of the Kostanay Region, Kostanay, Kazakhstan
| | - Kuanysh Zhumalynov
- Department of Natural Sciences, Akhmet Baitursynuly Kostanay Regional University, Kostanay, Kazakhstan
| | - Elizaveta Koneva
- Department of Sports Medicine and Medical Rehabilitation, Sechenov University, Moscow, Russia
| | - Natalia Afanasyeva
- Resource Center “Medical Sechenov Pre-University”, Sechenov University, Moscow, Russia
| | - Dmitri Borodulin
- Department of Technology of Storage and Processing of Fruits, Vegetables and Plant Growing Products, Russian State Agrarian University-Moscow Timiryazev Agricultural Academy, Moscow, Russia
| | | | - Almabek Nugmanov
- Department of Natural Sciences, Akhmet Baitursynuly Kostanay Regional University, Kostanay, Kazakhstan
| | - Murat Nurushev
- Higher School of Natural Sciences, Astana International University, Astana, Kazakhstan
| | - Vadim Chashkov
- Department of Natural Sciences, Akhmet Baitursynuly Kostanay Regional University, Kostanay, Kazakhstan
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Berber M, Penton D. Calcineurin inhibitors and the renin-angiotensin-aldosterone system. Acta Physiol (Oxf) 2024; 240:e14248. [PMID: 39460458 DOI: 10.1111/apha.14248] [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: 03/29/2024] [Revised: 10/07/2024] [Accepted: 10/11/2024] [Indexed: 10/28/2024]
Abstract
Calcineurin inhibitors (CnIs) are effective immunosuppressants with decades of accumulated experience in treating immune disorders and, most notably, solid organ transplantation. While CnIs have significantly increased graft survival and transformed the patient standard of care, their use has been overshadowed by a number of undesired side effects. For instance, CnI-associated nephrotoxicity has been reported since early studies and remains a major therapeutic concern. The occurrence of several ion imbalances alongside hypertension was also noted early on, indicating the involvement of the renin-angiotensin-aldosterone system (RAAS) in CnI-mediated toxicity. However, the literature in this field is crowded with conflicting reports from clinical trials as well as studies using animal and invitro models. With this review, we aim to provide a structured and updated overview of the physiological and pathophysiological evidence supporting the involvement of the classical RAAS in CnI-associated toxicity.
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Affiliation(s)
- Mesut Berber
- Department of Pediatrics, Harvard Medical School and Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - David Penton
- Electrophysiology Facility, University of Zurich, Zurich, Switzerland
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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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Akpoviroro O, Sauers NK, Uwandu Q, Castagne M, Akpoviroro OP, Humayun S, Mirza W, Woodard J. Severe COVID-19 infection: An institutional review and literature overview. PLoS One 2024; 19:e0304960. [PMID: 39163410 PMCID: PMC11335168 DOI: 10.1371/journal.pone.0304960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 05/21/2024] [Indexed: 08/22/2024] Open
Abstract
BACKGROUND Our study aimed to describe the group of severe COVID-19 patients at an institutional level, and determine factors associated with different outcomes. METHODS A retrospective chart review of patients admitted with severe acute hypoxic respiratory failure due to COVID-19 infection. Based on outcomes, we categorized 3 groups of severe COVID-19: (1) Favorable outcome: progressive care unit admission and discharge (2) Intermediate outcome: ICU care (3) Poor outcome: in-hospital mortality. RESULTS Eighty-nine patients met our inclusion criteria; 42.7% were female. The average age was 59.7 (standard deviation (SD):13.7). Most of the population were Caucasian (95.5%) and non-Hispanic (91.0%). Age, sex, race, and ethnicity were similar between outcome groups. Medicare and Medicaid patients accounted for 62.9%. The average BMI was 33.5 (SD:8.2). Moderate comorbidity was observed, with an average Charlson Comorbidity index (CCI) of 3.8 (SD:2.6). There were no differences in the average CCI between groups(p = 0.291). Many patients (67.4%) had hypertension, diabetes (42.7%) and chronic lung disease (32.6%). A statistical difference was found when chronic lung disease was evaluated; p = 0.002. The prevalence of chronic lung disease was 19.6%, 27.8%, and 40% in the favorable, intermediate, and poor outcome groups, respectively. Smoking history was associated with poor outcomes (p = 0.04). Only 7.9% were fully vaccinated. Almost half (46.1%) were intubated and mechanically ventilated. Patients spent an average of 12.1 days ventilated (SD:8.5), with an average of 6.0 days from admission to ventilation (SD:5.1). The intermediate group had a shorter average interval from admission to ventilator (77.2 hours, SD:67.6), than the poor group (212.8 hours, SD:126.8); (p = 0.001). The presence of bacterial pneumonia was greatest in the intermediate group (72.2%), compared to the favorable group (17.4%), and the poor group (56%); this was significant (p<0.0001). In-hospital mortality was seen in 28.1%. CONCLUSION Most patients were male, obese, had moderate-level comorbidity, a history of tobacco abuse, and government-funded insurance. Nearly 50% required mechanical ventilation, and about 28% died during hospitalization. Bacterial pneumonia was most prevalent in intubated groups. Patients who were intubated with a good outcome were intubated earlier during their hospital course, with an average difference of 135.6 hours. A history of cigarette smoking and chronic lung disease were associated with poor outcomes.
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Affiliation(s)
- Ogheneyoma Akpoviroro
- Department of Internal Medicine, Geisinger Wyoming Valley Medical Center, Wilkes-Barre, Pennsylvania, United States of America
| | - Nathan Kyle Sauers
- Department of Engineering, Pennsylvania State University, State College, Pennsylvania, United States of America
| | - Queeneth Uwandu
- Department of Internal Medicine, Geisinger Wyoming Valley Medical Center, Wilkes-Barre, Pennsylvania, United States of America
| | - Myriam Castagne
- Clinical & Translational Science Institute, Boston University, Boston, Massachusetts, United States of America
| | | | - Sara Humayun
- Department of Internal Medicine, Geisinger Wyoming Valley Medical Center, Wilkes-Barre, Pennsylvania, United States of America
| | - Wasique Mirza
- Department of Internal Medicine, Geisinger Wyoming Valley Medical Center, Wilkes-Barre, Pennsylvania, United States of America
| | - Jameson Woodard
- Department of Internal Medicine, Geisinger Wyoming Valley Medical Center, Wilkes-Barre, Pennsylvania, United States of America
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Lahane GP, Dhar A, Bhat A. Therapeutic approaches and novel antifibrotic agents in renal fibrosis: A comprehensive review. J Biochem Mol Toxicol 2024; 38:e23795. [PMID: 39132761 DOI: 10.1002/jbt.23795] [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: 01/25/2024] [Revised: 06/20/2024] [Accepted: 07/24/2024] [Indexed: 08/13/2024]
Abstract
Renal fibrosis (RF) is one of the underlying pathological conditions leading to progressive loss of renal function and end-stage renal disease (ESRD). Over the years, various therapeutic approaches have been explored to combat RF and prevent ESRD. Despite significant advances in understanding the underlying molecular mechanism(s), effective therapeutic interventions for RF are limited. Current therapeutic strategies primarily target these underlying mechanisms to halt or reverse fibrotic progression. Inhibition of transforming growth factor-β (TGF-β) signaling, a pivotal mediator of RF has emerged as a central strategy to manage RF. Small molecules, peptides, and monoclonal antibodies that target TGF-β receptors or downstream effectors have demonstrated potential in preclinical models. Modulating the renin-angiotensin system and targeting the endothelin system also provide established approaches for controlling fibrosis-related hemodynamic changes. Complementary to pharmacological strategies, lifestyle modifications, and dietary interventions contribute to holistic management. This comprehensive review aims to summarize the underlying mechanisms of RF and provide an overview of the therapeutic strategies and novel antifibrotic agents that hold promise in its treatment.
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Affiliation(s)
- Ganesh Panditrao Lahane
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad, Telangana, India
| | - Arti Dhar
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad, Telangana, India
| | - Audesh Bhat
- Centre for Molecular Biology, Central University of Jammu, Samba, Jammu and Kashmir, India
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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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11
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Ueno A, Onishi Y, Mise K, Yamaguchi S, Kanno A, Nojima I, Higuchi C, Uchida HA, Shikata K, Miyamoto S, Nakatsuka A, Eguchi J, Hida K, Katayama A, Watanabe M, Nakato T, Tone A, Teshigawara S, Matsuoka T, Kamei S, Murakami K, Shimizu I, Miyashita K, Ando S, Nunoue T, Wada J. Plasma angiotensin-converting enzyme 2 (ACE2) is a marker for renal outcome of diabetic kidney disease (DKD) (U-CARE study 3). BMJ Open Diabetes Res Care 2024; 12:e004237. [PMID: 38816205 PMCID: PMC11141182 DOI: 10.1136/bmjdrc-2024-004237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Accepted: 05/15/2024] [Indexed: 06/01/2024] Open
Abstract
INTRODUCTION ACE cleaves angiotensin I (Ang I) to angiotensin II (Ang II) inducing vasoconstriction via Ang II type 1 (AT1) receptor, while ACE2 cleaves Ang II to Ang (1-7) causing vasodilatation by acting on the Mas receptor. In diabetic kidney disease (DKD), it is still unclear whether plasma or urine ACE2 levels predict renal outcomes or not. RESEARCH DESIGN AND METHODS Among 777 participants with diabetes enrolled in the Urinary biomarker for Continuous And Rapid progression of diabetic nEphropathy study, the 296 patients followed up for 9 years were investigated. Plasma and urinary ACE2 levels were measured by the ELISA. The primary end point was a composite of a decrease of estimated glomerular filtration rate (eGFR) by at least 30% from baseline or initiation of hemodialysis or peritoneal dialysis. The secondary end points were a 30% increase or a 30% decrease in albumin-to-creatinine ratio from baseline to 1 year. RESULTS The cumulative incidence of the renal composite outcome was significantly higher in group 1 with lowest tertile of plasma ACE2 (p=0.040). Group 2 with middle and highest tertile was associated with better renal outcomes in the crude Cox regression model adjusted by age and sex (HR 0.56, 95% CI 0.31 to 0.99, p=0.047). Plasma ACE2 levels demonstrated a significant association with 30% decrease in ACR (OR 1.46, 95% CI 1.044 to 2.035, p=0.027) after adjusting for age, sex, systolic blood pressure, hemoglobin A1c, and eGFR. CONCLUSIONS Higher baseline plasma ACE2 levels in DKD were protective for development and progression of albuminuria and associated with fewer renal end points, suggesting plasma ACE2 may be used as a prognosis marker of DKD. TRIAL REGISTRATION NUMBER UMIN000011525.
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Affiliation(s)
- Asami Ueno
- Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yasuhiro Onishi
- Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Koki Mise
- Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Satoshi Yamaguchi
- Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Ayaka Kanno
- Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Ichiro Nojima
- Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Chigusa Higuchi
- Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Haruhito A Uchida
- Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kenichi Shikata
- Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Satoshi Miyamoto
- Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Atsuko Nakatsuka
- Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Jun Eguchi
- Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kazuyuki Hida
- Department of Diabetology and Metabolism, National Hospital Organization Okayama Medical Center, Okayama, Japan
| | - Akihiro Katayama
- Department of Diabetology and Metabolism, National Hospital Organization Okayama Medical Center, Okayama, Japan
| | - Mayu Watanabe
- Department of Diabetology and Metabolism, National Hospital Organization Okayama Medical Center, Okayama, Japan
| | - Tatsuaki Nakato
- Department of Internal Medicine, Okayama Saiseikai General Hospital, Okayama, Japan
| | - Atsuhito Tone
- Department of Internal Medicine, Okayama Saiseikai General Hospital, Okayama, Japan
| | | | - Takashi Matsuoka
- Department of Diabetic Medicine, Kurashiki Central Hospital, Kurashiki, Japan
| | - Shinji Kamei
- Department of Diabetic Medicine, Kurashiki Central Hospital, Kurashiki, Japan
| | - Kazutoshi Murakami
- Department of Diabetic Medicine, Kurashiki Central Hospital, Kurashiki, Japan
| | - Ikki Shimizu
- Sakakibara Heart Institute of Okayama, Okayama, Japan
| | | | | | | | - Jun Wada
- Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
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12
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Shukla AK, Awasthi K, Usman K, Banerjee M. Role of renin-angiotensin system/angiotensin converting enzyme-2 mechanism and enhanced COVID-19 susceptibility in type 2 diabetes mellitus. World J Diabetes 2024; 15:606-622. [PMID: 38680697 PMCID: PMC11045416 DOI: 10.4239/wjd.v15.i4.606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 01/22/2024] [Accepted: 02/27/2024] [Indexed: 04/11/2024] Open
Abstract
Coronavirus disease 2019 (COVID-19) is a disease that caused a global pandemic and is caused by infection of severe acute respiratory syndrome coronavirus 2 virus. It has affected over 768 million people worldwide, resulting in approximately 6900000 deaths. High-risk groups, identified by the Centers for Disease Control and Prevention, include individuals with conditions like type 2 diabetes mellitus (T2DM), obesity, chronic lung disease, serious heart conditions, and chronic kidney disease. Research indicates that those with T2DM face a heightened susceptibility to COVID-19 and increased mortality compared to non-diabetic individuals. Examining the renin-angiotensin system (RAS), a vital regulator of blood pressure and pulmonary stability, reveals the significance of the angiotensin-converting enzyme (ACE) and ACE2 enzymes. ACE converts angiotensin-I to the vasoconstrictor angiotensin-II, while ACE2 counters this by converting angiotensin-II to angiotensin 1-7, a vasodilator. Reduced ACE2 expression, common in diabetes, intensifies RAS activity, contributing to conditions like inflammation and fibrosis. Although ACE inhibitors and angiotensin receptor blockers can be therapeutically beneficial by increasing ACE2 levels, concerns arise regarding the potential elevation of ACE2 receptors on cell membranes, potentially facilitating COVID-19 entry. This review explored the role of the RAS/ACE2 mechanism in amplifying severe acute respiratory syndrome coronavirus 2 infection and associated complications in T2DM. Potential treatment strategies, including recombinant human ACE2 therapy, broad-spectrum antiviral drugs, and epigenetic signature detection, are discussed as promising avenues in the battle against this pandemic.
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Affiliation(s)
- Ashwin Kumar Shukla
- Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow 226007, Uttar Pradesh, India
| | - Komal Awasthi
- Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow 226007, Uttar Pradesh, India
| | - Kauser Usman
- Department of Medicine, King Georges’ Medical University, Lucknow 226003, Uttar Pradesh, India
| | - Monisha Banerjee
- Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow 226007, Uttar Pradesh, India
- Institute of Advanced Molecular Genetics, and Infectious Diseases (IAMGID), University of Lucknow, Lucknow 226007, Uttar Pradesh, India
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13
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Zhou AX, Jeansson M, He L, Wigge L, Tonelius P, Tati R, Cederblad L, Muhl L, Uhrbom M, Liu J, Björnson Granqvist A, Lerman LO, Betsholtz C, Hansen PBL. Renal Endothelial Single-Cell Transcriptomics Reveals Spatiotemporal Regulation and Divergent Roles of Differential Gene Transcription and Alternative Splicing in Murine Diabetic Nephropathy. Int J Mol Sci 2024; 25:4320. [PMID: 38673910 PMCID: PMC11050020 DOI: 10.3390/ijms25084320] [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: 03/01/2024] [Revised: 04/04/2024] [Accepted: 04/11/2024] [Indexed: 04/28/2024] Open
Abstract
Endothelial cell (EC) injury is a crucial contributor to the progression of diabetic kidney disease (DKD), but the specific EC populations and mechanisms involved remain elusive. Kidney ECs (n = 5464) were collected at three timepoints from diabetic BTBRob/ob mice and non-diabetic littermates. Their heterogeneity, transcriptional changes, and alternative splicing during DKD progression were mapped using SmartSeq2 single-cell RNA sequencing (scRNAseq) and elucidated through pathway, network, and gene ontology enrichment analyses. We identified 13 distinct transcriptional EC phenotypes corresponding to different kidney vessel subtypes, confirmed through in situ hybridization and immunofluorescence. EC subtypes along nephrons displayed extensive zonation related to their functions. Differential gene expression analyses in peritubular and glomerular ECs in DKD underlined the regulation of DKD-relevant pathways including EIF2 signaling, oxidative phosphorylation, and IGF1 signaling. Importantly, this revealed the differential alteration of these pathways between the two EC subtypes and changes during disease progression. Furthermore, glomerular and peritubular ECs also displayed aberrant and dynamic alterations in alternative splicing (AS), which is strongly associated with DNA repair. Strikingly, genes displaying differential transcription or alternative splicing participate in divergent biological processes. Our study reveals the spatiotemporal regulation of gene transcription and AS linked to DKD progression, providing insight into pathomechanisms and clues to novel therapeutic targets for DKD treatment.
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Affiliation(s)
- Alex-Xianghua Zhou
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, 43162 Mölndal, Sweden; (A.-X.Z.); (P.T.); (M.U.)
| | - Marie Jeansson
- Department of Medicine Huddinge, Karolinska Institutet, 141 52 Huddinge, Sweden; (M.J.); (J.L.)
- Department of Immunology, Genetics and Pathology, Uppsala University, 753 10 Uppsala, Sweden
| | - Liqun He
- Department of Medicine Huddinge, Karolinska Institutet, 141 52 Huddinge, Sweden; (M.J.); (J.L.)
- Department of Immunology, Genetics and Pathology, Uppsala University, 753 10 Uppsala, Sweden
| | - Leif Wigge
- Data Sciences and Quantitative Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, 43162 Mölndal, Sweden
| | - Pernilla Tonelius
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, 43162 Mölndal, Sweden; (A.-X.Z.); (P.T.); (M.U.)
| | - Ramesh Tati
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, 43162 Mölndal, Sweden; (A.-X.Z.); (P.T.); (M.U.)
| | - Linda Cederblad
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, 43162 Mölndal, Sweden; (A.-X.Z.); (P.T.); (M.U.)
| | - Lars Muhl
- Department of Medicine Huddinge, Karolinska Institutet, 141 52 Huddinge, Sweden; (M.J.); (J.L.)
| | - Martin Uhrbom
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, 43162 Mölndal, Sweden; (A.-X.Z.); (P.T.); (M.U.)
- Department of Medicine Huddinge, Karolinska Institutet, 141 52 Huddinge, Sweden; (M.J.); (J.L.)
| | - Jianping Liu
- Department of Medicine Huddinge, Karolinska Institutet, 141 52 Huddinge, Sweden; (M.J.); (J.L.)
| | - Anna Björnson Granqvist
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, 43162 Mölndal, Sweden; (A.-X.Z.); (P.T.); (M.U.)
| | - Lilach O. Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55902, USA;
| | - Christer Betsholtz
- Department of Medicine Huddinge, Karolinska Institutet, 141 52 Huddinge, Sweden; (M.J.); (J.L.)
- Department of Immunology, Genetics and Pathology, Uppsala University, 753 10 Uppsala, Sweden
| | - Pernille B. L. Hansen
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, 43162 Mölndal, Sweden; (A.-X.Z.); (P.T.); (M.U.)
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14
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Cadore NA, Lord VO, Recamonde-Mendoza M, Kowalski TW, Vianna FSL. Meta-analysis of Transcriptomic Data from Lung Autopsy and Cellular Models of SARS-CoV-2 Infection. Biochem Genet 2024; 62:892-914. [PMID: 37486510 DOI: 10.1007/s10528-023-10453-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 07/12/2023] [Indexed: 07/25/2023]
Abstract
Severe COVID-19 is a systemic disorder involving excessive inflammatory response, metabolic dysfunction, multi-organ damage, and several clinical features. Here, we performed a transcriptome meta-analysis investigating genes and molecular mechanisms related to COVID-19 severity and outcomes. First, transcriptomic data of cellular models of SARS-CoV-2 infection were compiled to understand the first response to the infection. Then, transcriptomic data from lung autopsies of patients deceased due to COVID-19 were compiled to analyze altered genes of damaged lung tissue. These analyses were followed by functional enrichment analyses and gene-phenotype association. A biological network was constructed using the disturbed genes in the lung autopsy meta-analysis. Central genes were defined considering closeness and betweenness centrality degrees. A sub-network phenotype-gene interaction analysis was performed. The meta-analysis of cellular models found genes mainly associated with cytokine signaling and other pathogen response pathways. The meta-analysis of lung autopsy tissue found genes associated with coagulopathy, lung fibrosis, multi-organ damage, and long COVID-19. Only genes DNAH9 and FAM216B were found perturbed in both meta-analyses. BLNK, FABP4, GRIA1, ATF3, TREM2, TPPP, TPPP3, FOS, ALB, JUNB, LMNA, ADRB2, PPARG, TNNC1, and EGR1 were identified as central elements among perturbed genes in lung autopsy and were found associated with several clinical features of severe COVID-19. Central elements were suggested as interesting targets to investigate the relation with features of COVID-19 severity, such as coagulopathy, lung fibrosis, and organ damage.
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Affiliation(s)
- Nathan Araujo Cadore
- Laboratory of Genomic Medicine, Center of Experimental Research, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
- Laboratory of Immunobiology and Immunogenetics, Department of Genetics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
- Post-Graduation Program in Genetics and Molecular Biology, Department of Genetics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Vinicius Oliveira Lord
- Laboratory of Genomic Medicine, Center of Experimental Research, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
- Centro Universitário CESUCA, Cachoeirinha, Brazil
| | - Mariana Recamonde-Mendoza
- Bioinformatics Core, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
- Institute of Informatics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Thayne Woycinck Kowalski
- Laboratory of Genomic Medicine, Center of Experimental Research, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
- Post-Graduation Program in Genetics and Molecular Biology, Department of Genetics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
- Centro Universitário CESUCA, Cachoeirinha, Brazil
- Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
| | - Fernanda Sales Luiz Vianna
- Laboratory of Genomic Medicine, Center of Experimental Research, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil.
- Laboratory of Immunobiology and Immunogenetics, Department of Genetics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
- Post-Graduation Program in Genetics and Molecular Biology, Department of Genetics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
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15
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Jahanshahi F, Jazayeri SB, Eraghi MM, Reis LO, Hamidikia M, Amiri S, Aghamir SMK. A narrative review on adverse drug reactions of COVID-19 treatments on the kidney. Open Med (Wars) 2024; 19:20230867. [PMID: 38584847 PMCID: PMC10996932 DOI: 10.1515/med-2023-0867] [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: 03/23/2022] [Revised: 11/01/2022] [Accepted: 11/18/2023] [Indexed: 04/09/2024] Open
Abstract
Studies showed that the respiratory is not the only system affected by coronavirus 2, while cardiovascular, digestive, and nervous systems, as well as essential organs such as the kidneys, can be affected by this virus. In this review, we have studied the epidemiology, clinical, and laboratory findings on COVID-19 infection renal involvement, mortality, physiopathology, remaining renal sequels after recovery, underlying renal disease, and renal injury due to its treatment. Also, protective measures for kidney injury are explained in three levels. Evidence of viral particles and genome in the urine and renal tubular cells and signs of damage such as microangiopathy, hypercoagulopathy, and fibrosis are found in COVID-19 patients. The result of this study showed, in hospitalized COVID-19 patients, that the rate of acute kidney injury (AKI) was up to 46%, with a mortality ranging from 11 to 96%. A considerable proportion of patients with AKI would remain on renal replacement therapy. Proteinuria and hematuria are observed in 87 and 75% patients, and increased Cr and glomerular filtration rate (GFR) <60 ml/min per 1.73 m2 are observed in 29.6 and 35.3% of the patients, respectively. Remedsivir is considered to have adverse effects on GFR. COVID-19 patients need special attention to prevent AKI. Those with underlying chronic kidney disease or AKI need proper and explicit evaluation and treatment to improve their prognosis and decrease mortality, which should not be limited to the hospitalization period.
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Affiliation(s)
- Fatemeh Jahanshahi
- Research Committee Member, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Urology Research Center, Tehran University of Medical Sciences, Sina Hospital, Tehran, Iran
| | - Seyed Behnam Jazayeri
- Students’ Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Mirahmadi Eraghi
- Urology Research Center, Tehran University of Medical Sciences, Sina Hospital, Tehran, Iran
- School of Medicine, Qeshm International Branch, Islamic Azad University, Qeshm, Iran
| | - Leonardo Oliveira Reis
- UroScience and Department of Surgery (Urology), School of Medical Sciences, University of Campinas, Unicamp, and Pontifical Catholic University of Campinas, PUC-Campinas, Campinas, São Paulo, Brazil
| | - Mahtab Hamidikia
- Research Committee Member, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shayan Amiri
- Rasool Akram Medical Complex, Iran University of Medical Sciences, Tehran, Iran
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16
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Cianfarini C, Hassler L, Wysocki J, Hassan A, Nicolaescu V, Elli D, Gula H, Ibrahim AM, Randall G, Henkin J, Batlle D. Soluble Angiotensin-Converting Enzyme 2 Protein Improves Survival and Lowers Viral Titers in Lethal Mouse Model of Severe Acute Respiratory Syndrome Coronavirus Type 2 Infection with the Delta Variant. Cells 2024; 13:203. [PMID: 38334597 PMCID: PMC10854654 DOI: 10.3390/cells13030203] [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: 12/22/2023] [Revised: 01/19/2024] [Accepted: 01/20/2024] [Indexed: 02/10/2024] Open
Abstract
Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) utilizes angiotensin-converting enzyme 2 (ACE2) as its main receptor for cell entry. We bioengineered a soluble ACE2 protein termed ACE2 618-DDC-ABD that has increased binding to SARS-CoV-2 and prolonged duration of action. Here, we investigated the protective effect of this protein when administered intranasally to k18-hACE2 mice infected with the aggressive SARS-CoV-2 Delta variant. k18-hACE2 mice were infected with the SARS-CoV-2 Delta variant by inoculation of a lethal dose (2 × 104 PFU). ACE2 618-DDC-ABD (10 mg/kg) or PBS was administered intranasally six hours prior and 24 and 48 h post-viral inoculation. All animals in the PBS control group succumbed to the disease on day seven post-infection (0% survival), whereas, in contrast, there was only one casualty in the group that received ACE2 618-DDC-ABD (90% survival). Mice in the ACE2 618-DDC-ABD group had minimal disease as assessed using a clinical score and stable weight, and both brain and lung viral titers were markedly reduced. These findings demonstrate the efficacy of a bioengineered soluble ACE2 decoy with an extended duration of action in protecting against the aggressive Delta SARS-CoV-2 variant. Together with previous work, these findings underline the universal protective potential against current and future emerging SARS-CoV-2 variants.
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Affiliation(s)
- Cosimo Cianfarini
- Division of Nephrology/Hypertension, Department of Medicine, Feinberg School of Medicine, Northwestern University, 710 North Fairbanks Court, Chicago, IL 60611, USA
- Charité Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Luise Hassler
- Division of Nephrology/Hypertension, Department of Medicine, Feinberg School of Medicine, Northwestern University, 710 North Fairbanks Court, Chicago, IL 60611, USA
| | - Jan Wysocki
- Division of Nephrology/Hypertension, Department of Medicine, Feinberg School of Medicine, Northwestern University, 710 North Fairbanks Court, Chicago, IL 60611, USA
| | - Abdelsabour Hassan
- Division of Nephrology/Hypertension, Department of Medicine, Feinberg School of Medicine, Northwestern University, 710 North Fairbanks Court, Chicago, IL 60611, USA
| | - Vlad Nicolaescu
- Howard Taylor Ricketts Laboratory, Department of Microbiology, The University of Chicago, Lemont, IL 60637, USA
| | - Derek Elli
- Howard Taylor Ricketts Laboratory, Department of Microbiology, The University of Chicago, Lemont, IL 60637, USA
| | - Haley Gula
- Howard Taylor Ricketts Laboratory, Department of Microbiology, The University of Chicago, Lemont, IL 60637, USA
| | - Amany M. Ibrahim
- Howard Taylor Ricketts Laboratory, Department of Microbiology, The University of Chicago, Lemont, IL 60637, USA
| | - Glenn Randall
- Howard Taylor Ricketts Laboratory, Department of Microbiology, The University of Chicago, Lemont, IL 60637, USA
| | - Jack Henkin
- Center for Developmental Therapeutics, Northwestern University, Evanston, IL 60208, USA
| | - Daniel Batlle
- Division of Nephrology/Hypertension, Department of Medicine, Feinberg School of Medicine, Northwestern University, 710 North Fairbanks Court, Chicago, IL 60611, USA
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17
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Chen CY, Lin MW, Xie XY, Lin CH, Yang CW, Wu PC, Liu DH, Wu CJ, Lin CS. Studying the Roles of the Renin-Angiotensin System in Accelerating the Disease of High-Fat-Diet-Induced Diabetic Nephropathy in a db/db and ACE2 Double-Gene-Knockout Mouse Model. Int J Mol Sci 2023; 25:329. [PMID: 38203500 PMCID: PMC10779113 DOI: 10.3390/ijms25010329] [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: 11/15/2023] [Revised: 12/20/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
Diabetic nephropathy (DN) is a crucial metabolic health problem. The renin-angiotensin system (RAS) is well known to play an important role in DN. Abnormal RAS activity can cause the over-accumulation of angiotensin II (Ang II). Angiotensin-converting enzyme inhibitor (ACEI) administration has been proposed as a therapy, but previous studies have also indicated that chymase, the enzyme that hydrolyzes angiotensin I to Ang II in an ACE-independent pathway, may play an important role in the progression of DN. Therefore, this study established a model of severe DN progression in a db/db and ACE2 KO mouse model (db and ACE2 double-gene-knockout mice) to explore the roles of RAS factors in DNA and changes in their activity after short-term (only 4 weeks) feeding of a high-fat diet (HFD) to 8-week-old mice. The results indicate that FD-fed db/db and ACE2 KO mice fed an HFD represent a good model for investigating the role of RAS in DN. An HFD promotes the activation of MAPK, including p-JNK and p-p38, as well as the RAS signaling pathway, leading to renal damage in mice. Blocking Ang II/AT1R could alleviate the progression of DN after administration of ACEI or chymase inhibitor (CI). Both ACE and chymase are highly involved in Ang II generation in HFD-induced DN; therefore, ACEI and CI are potential treatments for DN.
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Affiliation(s)
- Cheng-Yi Chen
- Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Hsinchu 300, Taiwan;
- MacKay Junior College of Medicine, Nursing and Management, Taipei 112, Taiwan
| | - Meng-Wei Lin
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan; (M.-W.L.); (X.-Y.X.); (C.-H.L.)
| | - Xing-Yang Xie
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan; (M.-W.L.); (X.-Y.X.); (C.-H.L.)
| | - Cheng-Han Lin
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan; (M.-W.L.); (X.-Y.X.); (C.-H.L.)
| | - Chung-Wei Yang
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu 300, Taiwan;
| | - Pei-Ching Wu
- Doctoral Degree Program of Biomedical Science and Engineering, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan; (P.-C.W.); (D.-H.L.)
- Department of Chinese Medicine, China Medical University Hospital, Taichung 404, Taiwan
| | - Dung-Huan Liu
- Doctoral Degree Program of Biomedical Science and Engineering, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan; (P.-C.W.); (D.-H.L.)
- Department of Physical Medicine and Rehabilitation, China Medical University Hospital, Taichung 404, Taiwan
| | - Chih-Jen Wu
- Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei 100, Taiwan
- Division of Medicine, College of Medicine, Taipei Medical University, Taipei 100, Taiwan
| | - Chih-Sheng Lin
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan; (M.-W.L.); (X.-Y.X.); (C.-H.L.)
- Doctoral Degree Program of Biomedical Science and Engineering, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan; (P.-C.W.); (D.-H.L.)
- Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
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18
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Guo N, Li X, Han Z, Yu Q, Zhang Y, Liu S, Xu H, Han G, Li Q. Expression of angiotensin converting enzyme 2 mRNA in different SARS-CoV-2 infection states and times. J Biomol Struct Dyn 2023; 41:11255-11261. [PMID: 36625725 DOI: 10.1080/07391102.2022.2160821] [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: 08/26/2022] [Accepted: 12/15/2022] [Indexed: 01/11/2023]
Abstract
To measure the expression of angiotensin converting enzyme 2 (ACE2) mRNA in SARS-CoV-2 infection with different infection status and at different stages during infection, we used RT-qP CR to measure the expression of ACE2 mRNA. Measurements were analyzed by two-way repeated measures analysis of variance (RMANOVA). Expression of ACE2 mRNA was downregulated in initial stages of SARS-CoV-2 infection both in the asymptomatic infection (ASY) group and the confirmed cases (CON) group (t=-8.0845, P < 0.0001; t=-8.1904, P < 0.0001, respectively). The expression of ACE2 mRNA in the incubation period of CON group was lower compared with the intinal period of ASY group (F = 6.084, p = 0.016, partialη2 = 0.070). Relative expression of ACE2 mRNA was upregulated at the late stage of SARS-CoV-2 infection in the ASY and CON groups (F = 23.489, p = 0.000, partialη2 = 0.225; F = 46.555, p = 0.000, partialη2 = 0.365, respectively). The relative expression of ACE2 mRNA was down-regulated (mean ± SEM:0.69 ± 0.03) after inoculation with SARSCoV- 2 Spike pseudovirus, and there was a statistical difference (one-way t test, mean diffience =-0.31, 95%CI: -0.37˜-0.24, t=-8.1904, P < 0.0001). The expression of ACE2 mRNA is downregulated in the initial stage of SARS-CoV-2 infection, and then upregulated in the late stage of SARS-CoV-2 infection. The lower expression of ACE2 mRNA during the incubation period can lead to clinical symptoms. Downregulation of ACE2 mRNA was related to the interaction between SARS-CoV-2 S protein and ACE2.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Nana Guo
- Hebei Medical University, Shijiazhang, People's Republic of China
- bHandan Center for Disease Control and Prevention, Handan, People's Republic of China
| | - Xue Li
- Hebei Medical University, Shijiazhang, People's Republic of China
| | - Zhanying Han
- Hebei Provincial Center for Disease Control and Prevention, Shijiazhang, People's Republic of China
| | - Qiuli Yu
- Hebei Provincial Center for Disease Control and Prevention, Shijiazhang, People's Republic of China
| | - Yanbo Zhang
- Hebei Provincial Center for Disease Control and Prevention, Shijiazhang, People's Republic of China
| | - Shiyou Liu
- Hebei Provincial Center for Disease Control and Prevention, Shijiazhang, People's Republic of China
| | - Han Xu
- Hebei Provincial Center for Disease Control and Prevention, Shijiazhang, People's Republic of China
| | - Guangyue Han
- Hebei Provincial Center for Disease Control and Prevention, Shijiazhang, People's Republic of China
| | - Qi Li
- Hebei Medical University, Shijiazhang, People's Republic of China
- Hebei Provincial Center for Disease Control and Prevention, Shijiazhang, People's Republic of China
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19
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Thakur A, Sharma V, Averbek S, Liang L, Pandya N, Kumar G, Cili A, Zhang K. Immune landscape and redox imbalance during neurological disorders in COVID-19. Cell Death Dis 2023; 14:593. [PMID: 37673862 PMCID: PMC10482955 DOI: 10.1038/s41419-023-06102-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 08/13/2023] [Accepted: 08/22/2023] [Indexed: 09/08/2023]
Abstract
The outbreak of Coronavirus Disease 2019 (COVID-19) has prompted the scientific community to explore potential treatments or vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes the illness. While SARS-CoV-2 is mostly considered a respiratory pathogen, several neurological complications have been reported, raising questions about how it may enter the Central Nervous System (CNS). Receptors such as ACE2, CD147, TMPRSS2, and NRP1 have been identified in brain cells and may be involved in facilitating SARS-CoV-2 entry into the CNS. Moreover, proteins like P2X7 and Panx-1 may contribute to the pathogenesis of COVID-19. Additionally, the role of the immune system in the gravity of COVID-19 has been investigated with respect to both innate and adaptive immune responses caused by SARS-CoV-2 infection, which can lead to a cytokine storm, tissue damage, and neurological manifestations. A redox imbalance has also been linked to the pathogenesis of COVID-19, potentially causing mitochondrial dysfunction, and generating proinflammatory cytokines. This review summarizes different mechanisms of reactive oxygen species and neuro-inflammation that may contribute to the development of severe COVID-19, and recent progress in the study of immunological events and redox imbalance in neurological complications of COVID-19, and the role of bioinformatics in the study of neurological implications of COVID-19.
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Affiliation(s)
- Abhimanyu Thakur
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation-CAS Limited, Hong Kong SAR, Hong Kong.
| | - Vartika Sharma
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Sera Averbek
- GSI Helmholtzzentrum für Schwerionenforschung GmbH, Darmstadt, Germany
- Technische Universität Darmstadt, Darmstadt, Germany
| | - Lifan Liang
- University of Pittsburgh, Pittsburgh, PA, USA
| | - Nirali Pandya
- Department of Chemistry, Faculty of Sciences, National University of Singapore, Singapore, Singapore
| | - Gaurav Kumar
- School of Biosciences and Biomedical Engineering, Department of Clinical Research, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Alma Cili
- Clinic of Hematology, University of Medicine, University Hospital center "Mother Teresa", Tirane, Albania
| | - Kui Zhang
- State Key Laboratory of Resource Insects, College of Sericulture, Textile and Biomass sciences, Southwest University, Chongqing, China.
- Cancer Centre, Medical Research Institute, Southwest University, Chongqing, China.
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20
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Abstract
Sequential expression of claudins, a family of tight junction proteins, along the nephron mirrors the sequential expression of ion channels and transporters. Only by the interplay of transcellular and paracellular transport can the kidney efficiently maintain electrolyte and water homeostasis in an organism. Although channel and transporter defects have long been known to perturb homeostasis, the contribution of individual tight junction proteins has been less clear. Over the past two decades, the regulation and dysregulation of claudins have been intensively studied in the gastrointestinal tract. Claudin expression patterns have, for instance, been found to be affected in infection and inflammation, or in cancer. In the kidney, a deeper understanding of the causes as well as the effects of claudin expression alterations is only just emerging. Little is known about hormonal control of the paracellular pathway along the nephron, effects of cytokines on renal claudin expression or relevance of changes in paracellular permeability to the outcome in any of the major kidney diseases. By summarizing current findings on the role of specific claudins in maintaining electrolyte and water homeostasis, this Review aims to stimulate investigations on claudins as prognostic markers or as druggable targets in kidney disease.
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Affiliation(s)
- Luca Meoli
- Clinical Physiology/Nutritional Medicine, Medical Department, Division of Gastroenterology, Infectiology, Rheumatology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Dorothee Günzel
- Clinical Physiology/Nutritional Medicine, Medical Department, Division of Gastroenterology, Infectiology, Rheumatology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
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21
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Wang CW, Chuang HC, Tan TH. ACE2 in chronic disease and COVID-19: gene regulation and post-translational modification. J Biomed Sci 2023; 30:71. [PMID: 37608279 PMCID: PMC10464117 DOI: 10.1186/s12929-023-00965-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 08/15/2023] [Indexed: 08/24/2023] Open
Abstract
Angiotensin-converting enzyme 2 (ACE2), a counter regulator of the renin-angiotensin system, provides protection against several chronic diseases. Besides chronic diseases, ACE2 is the host receptor for SARS-CoV or SARS-CoV-2 virus, mediating the first step of virus infection. ACE2 levels are regulated by transcriptional, post-transcriptional, and post-translational regulation or modification. ACE2 transcription is enhanced by transcription factors including Ikaros, HNFs, GATA6, STAT3 or SIRT1, whereas ACE2 transcription is reduced by the transcription factor Brg1-FoxM1 complex or ERRα. ACE2 levels are also regulated by histone modification or miRNA-induced destabilization. The protein kinase AMPK, CK1α, or MAP4K3 phosphorylates ACE2 protein and induces ACE2 protein levels by decreasing its ubiquitination. The ubiquitination of ACE2 is induced by the E3 ubiquitin ligase MDM2 or UBR4 and decreased by the deubiquitinase UCHL1 or USP50. ACE2 protein levels are also increased by the E3 ligase PIAS4-mediated SUMOylation or the methyltransferase PRMT5-mediated ACE2 methylation, whereas ACE2 protein levels are decreased by AP2-mediated lysosomal degradation. ACE2 is downregulated in several human chronic diseases like diabetes, hypertension, or lung injury. In contrast, SARS-CoV-2 upregulates ACE2 levels, enhancing host cell susceptibility to virus infection. Moreover, soluble ACE2 protein and exosomal ACE2 protein facilitate SARS-CoV-2 infection into host cells. In this review, we summarize the gene regulation and post-translational modification of ACE2 in chronic disease and COVID-19. Understanding the regulation and modification of ACE2 may help to develop prevention or treatment strategies for ACE2-mediated diseases.
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Affiliation(s)
- Chia-Wen Wang
- Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan, 35053 Taiwan
| | - Huai-Chia Chuang
- Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan, 35053 Taiwan
| | - Tse-Hua Tan
- Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan, 35053 Taiwan
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22
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Al Abri SY, Burad J, Al Wahaibi MM. The Incidence of Acute Kidney Injury (AKI) in Critically Ill COVID-19 Patients: A Single-Center Retrospective Cohort Study at a Tertiary Level Hospital in Oman. Cureus 2023; 15:e40340. [PMID: 37456444 PMCID: PMC10338890 DOI: 10.7759/cureus.40340] [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] [Accepted: 06/12/2023] [Indexed: 07/18/2023] Open
Abstract
BACKGROUND Acute kidney injury (AKI) is associated with adverse outcomes in critically ill patients. Coronavirus disease 2019 (COVID-19) affects the renal system frequently and leads to AKI. This study aims to determine the incidence of AKI, risk factors including hyperglycemia, and the requirement for renal dialysis. METHODS A retrospectively observational study was done at Sultan Qaboos University Hospital between March 2020 and September 2021. A total of 286 adult patients with laboratory-confirmed COVID-19 infection admitted to the intensive care unit (ICU) were included in the study. The patient's medical records were reviewed. Patients' baseline demographic characteristics, APACHE score on admission, clinical data including length of stay, oxygenation parameters, ventilator days, shock, AKI (KIDIGO guideline), dialysis, medications, lab on admission as well as during the ICU stay, and the outcome (mortality) were recorded in detail. Follow-up was done till discharge from ICU. RESULTS The study population included 68.5% (196/286) males. The median age was 56 years (interquartile range, IQR: 43-66.25). The incidence of AKI was 55.2% (158/286) overall. Out of those who had AKI, 27.2% (43/158), 31.6% (50/158), and 41.1% (65/158) developed AKI stages 1, 2, and 3, respectively. Univariate analysis for the development of AKI showed the following significant variables: age (p=0.005; odds ratio, OR 1.024; 95% confidence interval, CI 1.007-1.041), creatinine level on admission (p=0.012; OR 1.005; 95%CI 1.001-1.008), APACHE score on admission (p<0.001; OR 1.049; 95%CI 1.021-1.077), P/F ratio (p<0.001; OR 0.991; 95%CI 0.987-0.995), nephrotoxic agent (p<0.001; OR 8.556; 95%CI 4.733-15.467), shock (p<0.001; OR 8.690; 95%CI 5.087-14.843), days on the ventilator (p<0.001; OR 1.085; 95%CI 1.043-1.129), and length of stay in ICU (p<0.001; OR 1.082; 95%CI 1.047-1.119). The multivariate analysis confirmed only shock (p=0.004; OR 5.893; 95%CI 1.766-19.664). A total of 41.7% (66/158) of patients received dialysis. Hyperglycemia was not associated with the development of AKI. For patients with AKI, those having high APACHE score (p<0.001), shock (p=0.56; OR 2.326; 95%CI 1.036-5.223), ischemic heart disease (IHD) (p=0.002; OR 9.000; 95%CI 1.923-42.130), and hypertension (p=0.023; OR 2.145; 95%CI 11.125-4.090) were significantly associated with the requirement of dialysis. The mortality was found to be 59.1% (169/286) overall whereas it was 83.5% (132/158) for AKI versus 28.9% (37/158) for non-AKI cases. CONCLUSIONS A high incidence of AKI for critically ill COVID-19 cases was found in this study. The shock was the only significant predictor for the development of AKI. AKI is associated with high mortality in these patients.
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Affiliation(s)
- Sulaiman Y Al Abri
- Anesthesia and Intensive Care, Oman Medical Specialty Board, Muscat, OMN
| | - Jyoti Burad
- Anesthesia and Intensive Care, Sultan Qaboos University Hospital, Muscat, OMN
| | - Mazin M Al Wahaibi
- Anesthesia and Intensive Care, Oman Medical Specialty Board, Muscat, OMN
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23
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D'Souza F, Buzzetti R, Pozzilli P. Diabetes, COVID-19, and questions unsolved. Diabetes Metab Res Rev 2023:e3666. [PMID: 37209039 DOI: 10.1002/dmrr.3666] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 04/13/2023] [Accepted: 05/05/2023] [Indexed: 05/22/2023]
Abstract
Recent evidence suggests a role for Diabetes Mellitus in adverse outcomes from COVID-19 infection; yet the underlying mechanisms are not clear. Moreover, attention has turned to prophylactic vaccination to protect the population from COVID-19-related illness and mortality. We performed a comprehensive peer-reviewed literature search on an array of key terms concerning diabetes and COVID-19 seeking to address the following questions: 1. What role does diabetes play as an accelerator for adverse outcomes in COVID-19?; 2. What mechanisms underlie the differences in outcomes seen in people with diabetes?; 3. Are vaccines against COVID-19 efficacious in people with diabetes? The current literature demonstrates that diabetes is associated with an increased risk of adverse outcomes from COVID-19 infection, and post-COVID sequelae. Potential mechanisms include dysregulation of Angiotensin Converting Enzyme 2, Furin, CD147, and impaired immune cell responses. Hyperglycaemia is a key exacerbator of these mechanisms. Limited studies are available on COVID-19 vaccination in people with diabetes; however, the current literature suggests that vaccination is protective against adverse outcomes for this population. In summary, people with diabetes are a high-risk group that should be prioritised in vaccination efforts. Glycaemic optimisation is paramount to protecting this group from COVID-19-associated risk. Unsolved questions remain as to the molecular mechanisms underlying the adverse outcomes seen in people with diabetes; the functional impact of post-COVID symptoms on people with diabetes, their persistence, and management; how long-term vaccine efficacy is affected by diabetes, and the antibody levels that confer protection from adverse outcomes in COVID-19.
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Affiliation(s)
- Felecia D'Souza
- University College London Hospitals NHS Trust, London, UK
- Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Raffaella Buzzetti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Paolo Pozzilli
- Department of Endocrinology & Diabetes, University Campus Bio-Medico, Rome, Italy
- Centre for Immunobiology, Barts and the London School of Medicine, Queen Mary University of London, London, UK
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24
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Mohammedsaeed W, Ahmedseedi I, Alahmadey Z. Liver and Renal Impairments in COVID-19 Patients of Madinah City of Saudi Arabia: A Cross-Sectional Study (2020). Cureus 2023; 15:e39409. [PMID: 37362525 PMCID: PMC10287181 DOI: 10.7759/cureus.39409] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/22/2023] [Indexed: 06/28/2023] Open
Abstract
Purpose Most of the research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease 2019 [COVID-19]) has mainly focused on the lungs as a key organ involved in the disease, while very little data is available regarding the involvement of other organs including the liver and kidneys, which are also reported to be severely affected by the disease. The objective of this study was to analyze the effect of COVID-19 disease on liver and kidney functions and to determine their association with the severity and mortality of the disease. This was a retrospective cross-sectional analysis of medical records. Methods A total of 100 confirmed COVID-19 adult patients from Madinah, Saudi Arabia hospitalized between April 28 and June 30, 2020, were included and categorized into asymptomatic, mild to moderate, and severely ill patients. We analyzed the clinical status of liver and renal functioning in all three groups. Results Most patients (51%) were diagnosed with mild to moderate disease, 27% of patients were severely ill and 22% of patients were asymptomatic. The liver and renal functional analysis showed that the severity of the COVID-19 patients was significantly associated with renal impairments exhibiting higher levels of creatinine and urea (P<0.05) with high levels of liver enzymes as indicators for liver damage. Conclusion We concluded from the present study that severely ill COVID-19 patients were more prone to have abnormal liver and renal functions. The present findings, however, demand further study of the association between liver and kidney impairments with COVID-19 infection for better clinical management.
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Affiliation(s)
- Walaa Mohammedsaeed
- Department of Medical Laboratory Technology, Faculty of Applied Medical Science, Taibah University, Madinah, SAU
| | | | - Ziab Alahmadey
- Laboratory Department, Ohud Hospital Madinah, Madinah, SAU
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25
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Zhang T, Wang N, Zhu L, Chen L, Liu H. Bidirectional Relationship between Glycemic Control and COVID-19 and Perspectives of Islet Organoid Models of SARS-CoV-2 Infection. Biomedicines 2023; 11:biomedicines11030856. [PMID: 36979836 PMCID: PMC10045433 DOI: 10.3390/biomedicines11030856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 02/21/2023] [Accepted: 03/07/2023] [Indexed: 03/16/2023] Open
Abstract
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to morbidity and mortality, with several clinical manifestations, and has caused a widespread pandemic. It has been found that type 2 diabetes is a risk factor for severe coronavirus disease 2019 (COVID-19) illness. Moreover, accumulating evidence has shown that SARS-CoV-2 infection can increase the risk of hyperglycemia and diabetes, though the underlying mechanism remains unclear because of a lack of authentic disease models to recapitulate the abnormalities involved in the development, regeneration, and function of human pancreatic islets under SARS-CoV-2 infection. Stem-cell-derived islet organoids have been valued as a model to study islets’ development and function, and thus provide a promising model for unraveling the mechanisms underlying the onset of diabetes under SARS-CoV-2 infection. This review summarized the latest results from clinical and basic research on SARS-CoV-2-induced pancreatic islet damage and impaired glycemic control. Furthermore, we discuss the potential and perspectives of using human ES/iPS cell-derived islet organoids to unravel the bidirectional relationship between glycemic control and SARS-CoV-2 infection.
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Affiliation(s)
- Tongran Zhang
- Guangzhou Laboratory, Guangzhou 510006, China; (T.Z.); (N.W.)
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China;
| | - Nannan Wang
- Guangzhou Laboratory, Guangzhou 510006, China; (T.Z.); (N.W.)
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Lingqiang Zhu
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China;
| | - Lihua Chen
- Guangzhou Laboratory, Guangzhou 510006, China; (T.Z.); (N.W.)
- School of Biomedical Engineering, Guangzhou Medical University, Guangzhou 510180, China
- Correspondence: (L.C.); (H.L.)
| | - Huisheng Liu
- Guangzhou Laboratory, Guangzhou 510006, China; (T.Z.); (N.W.)
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
- School of Biomedical Engineering, Guangzhou Medical University, Guangzhou 510180, China
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 510006, China
- Correspondence: (L.C.); (H.L.)
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26
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Isnard P, Vergnaud P, Garbay S, Jamme M, Eloudzeri M, Karras A, Anglicheau D, Galantine V, Jalal Eddine A, Gosset C, Pourcine F, Zarhrate M, Gibier JB, Rensen E, Pietropaoli S, Barba-Spaeth G, Duong-Van-Huyen JP, Molina TJ, Mueller F, Zimmer C, Pontoglio M, Terzi F, Rabant M. A specific molecular signature in SARS-CoV-2-infected kidney biopsies. JCI Insight 2023; 8:165192. [PMID: 36749641 PMCID: PMC10077488 DOI: 10.1172/jci.insight.165192] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 01/25/2023] [Indexed: 02/08/2023] Open
Abstract
Acute kidney injury is one of the most important complications in patients with COVID-19 and is considered a negative prognostic factor with respect to patient survival. The occurrence of direct infection of the kidney by SARS-CoV-2, and its contribution to the renal deterioration process, remain controversial issues. By studying 32 renal biopsies from patients with COVID-19, we verified that the major pathological feature of COVID-19 is acute tubular injury (ATI). Using single-molecule fluorescence in situ hybridization, we showed that SARS-CoV-2 infected living renal cells and that infection, which paralleled renal angiotensin-converting enzyme 2 expression levels, was associated with increased death. Mechanistically, a transcriptomic analysis uncovered specific molecular signatures in SARS-CoV-2-infected kidneys as compared with healthy kidneys and non-COVID-19 ATI kidneys. On the other hand, we demonstrated that SARS-CoV-2 and hantavirus, 2 RNA viruses, activated different genetic networks despite triggering the same pathological lesions. Finally, we identified X-linked inhibitor of apoptosis-associated factor 1 as a critical target of SARS-CoV-2 infection. In conclusion, this study demonstrated that SARS-CoV-2 can directly infect living renal cells and identified specific druggable molecular targets that can potentially aid in the design of novel therapeutic strategies to preserve renal function in patients with COVID-19.
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Affiliation(s)
- Pierre Isnard
- University of Paris Cité, INSERM U1151, CNRS UMR 8253, Institut Necker-Enfants Malades, Département Croissance et Signalisation, Paris, France.,Department of Pathology, Centre Hospitalier Universitaire Necker-Enfants Malades, Assistance Publique - Hopitaux de Paris (AP-HP), Paris, France
| | - Paul Vergnaud
- University of Paris Cité, INSERM U1151, CNRS UMR 8253, Institut Necker-Enfants Malades, Département Croissance et Signalisation, Paris, France
| | - Serge Garbay
- University of Paris Cité, INSERM U1151, CNRS UMR 8253, Institut Necker-Enfants Malades, Département Croissance et Signalisation, Paris, France
| | - Matthieu Jamme
- Department of Intensive Care Medicine, Centre Hospitalier Intercommunal de Poissy, Poissy, France
| | - Maeva Eloudzeri
- University of Paris Cité, INSERM U1151, CNRS UMR 8253, Institut Necker-Enfants Malades, Département Croissance et Signalisation, Paris, France
| | - Alexandre Karras
- Department of Nephrology, Centre Hospitalier Universitaire Européen Georges Pompidou, Paris, France
| | - Dany Anglicheau
- University of Paris Cité, INSERM U1151, CNRS UMR 8253, Institut Necker-Enfants Malades, Département Croissance et Signalisation, Paris, France.,Department of Transplantation, Centre Hospitalier Universitaire Necker-Enfants Malades, Paris, France
| | - Valérie Galantine
- Department of Nephrology, Centre Hospitalier Universitaire de la Guadeloupe, Pointe-à-Pitre, France
| | | | - Clément Gosset
- Department of Nephrology, Centre Hospitalier Universitaire de La Réunion, Saint Denis de La Réunion, France
| | - Franck Pourcine
- Department of Nephrology, Centre Hospitalier de Melun, Melun, France
| | - Mohammed Zarhrate
- Genomics Core Facility, Structure Fédérative de Recherche Necker, University of Paris, Paris, France
| | - Jean-Baptiste Gibier
- Department of Pathology, Centre Hospitalier Universitaire (CHU) Lille, Lille, France
| | | | | | | | - Jean-Paul Duong-Van-Huyen
- Department of Pathology, Centre Hospitalier Universitaire Necker-Enfants Malades, Assistance Publique - Hopitaux de Paris (AP-HP), Paris, France
| | - Thierry J Molina
- Department of Pathology, Centre Hospitalier Universitaire Necker-Enfants Malades, Assistance Publique - Hopitaux de Paris (AP-HP), Paris, France
| | | | | | - Marco Pontoglio
- University of Paris Cité, INSERM U1151, CNRS UMR 8253, Institut Necker-Enfants Malades, Département Croissance et Signalisation, Paris, France
| | - Fabiola Terzi
- University of Paris Cité, INSERM U1151, CNRS UMR 8253, Institut Necker-Enfants Malades, Département Croissance et Signalisation, Paris, France
| | - Marion Rabant
- University of Paris Cité, INSERM U1151, CNRS UMR 8253, Institut Necker-Enfants Malades, Département Croissance et Signalisation, Paris, France.,Department of Pathology, Centre Hospitalier Universitaire Necker-Enfants Malades, Assistance Publique - Hopitaux de Paris (AP-HP), Paris, France
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27
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Pan J, Gao Y, Han H, Pan T, Guo J, Li S, Xu J, Li Y. Multi-omics characterization of RNA binding proteins reveals disease comorbidities and potential drugs in COVID-19. Comput Biol Med 2023; 155:106651. [PMID: 36805221 PMCID: PMC9916187 DOI: 10.1016/j.compbiomed.2023.106651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 02/02/2023] [Accepted: 02/08/2023] [Indexed: 02/12/2023]
Abstract
The COVID-19 has led to a devastating global health crisis, which emphasizes the urgent need to deepen our understanding of the molecular mechanism and identifying potential antiviral drugs. Here, we comprehensively analyzed the transcriptomic and proteomic profiles of 178 COVID-19 patients, ranging from asymptomatic to critically ill. Our analyses found that the RNA binding proteins (RBPs) were likely to be perturbed in infection. Interactome analysis revealed that RBPs interact with virus proteins and the viral interacting RBPs were likely to locate in central regions of human protein-protein interaction network. Functional enrichment analysis revealed that the viral interacting RBPs were likely to be enriched in RNA transport, apoptosis and viral genome replication-related pathways. Based on network proximity analyses of 299 human complex-disease genes and COVID-19-related RBPs in the human interactome, we revealed the significant associations between complex diseases and COVID-19. Network analysis also implicated potential antiviral drugs for treatment of COVID-19. In summary, our integrative characterization of COVID-19 patients may thus help providing evidence regarding pathophysiology and potential therapeutic strategies for COVID-19.
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Affiliation(s)
- Jiwei Pan
- NHC Key Laboratory of Tropical Disease Control, College of Biomedical Information and Engineering, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou, 571199, China
| | - Yueying Gao
- NHC Key Laboratory of Tropical Disease Control, College of Biomedical Information and Engineering, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou, 571199, China
| | - Huirui Han
- NHC Key Laboratory of Tropical Disease Control, College of Biomedical Information and Engineering, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou, 571199, China
| | - Tao Pan
- NHC Key Laboratory of Tropical Disease Control, College of Biomedical Information and Engineering, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou, 571199, China
| | - Jing Guo
- NHC Key Laboratory of Tropical Disease Control, College of Biomedical Information and Engineering, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou, 571199, China
| | - Si Li
- NHC Key Laboratory of Tropical Disease Control, College of Biomedical Information and Engineering, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou, 571199, China
| | - Juan Xu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
| | - Yongsheng Li
- NHC Key Laboratory of Tropical Disease Control, College of Biomedical Information and Engineering, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou, 571199, China.
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Staico MF, Zaffanello M, DI Pietro G, Fanos V, Marcialis MA. The kidney in COVID-19: protagonist or figurant? Panminerva Med 2023; 65:65-75. [PMID: 32432445 DOI: 10.23736/s0031-0808.20.03965-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The etiology of injury in COVID-19 patients is diverse and multifactorial. Autopsy and biopsy studies reveal, alongside podocyte and tubular cell anomalies, the presence of virion within the cells. Evidence suggests that, in addition to the direct cytopathic effect of SARS-CoV-2 on the glomeruli and renal tubules, there is also the indirect effect of cell-mediated immunity, the cytokines storm and the cross-talk between organs with possible systemic effects of the disease. These mechanisms are interconnected and have profound therapeutic implications involving extracorporeal removal of inflammatory cytokines. Dialysis patients, and children, in particular, should be classified as "at high risk" of contracting the disease. Infections are one of the most frequent causes of death in children with chronic renal failure who undergo dialysis. The reasons for this particular susceptibility are to be found in the compromised immune system, secondary to chronic malnutrition, immunosuppressive therapy, and uremia, frequent contact with healthcare personnel and other patients attending the dialysis unit and in need of the presence of other family members during treatment.
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Affiliation(s)
- Maria F Staico
- School of Pediatrics, University of Cagliari, Cagliari, Italy
| | - Marco Zaffanello
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy -
| | | | - Vassilios Fanos
- School of Pediatrics, University of Cagliari, Cagliari, Italy.,Department of Surgery, University of Cagliari, Cagliari, Italy.,Neonatal Intensive Care Unit, AOU Cagliari, Cagliari, Italy
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Younis T, Jabeen F, Hussain A, Rasool B, Raza Ishaq A, Nawaz A, El-Nashar HAS, El-Shazly M. Antioxidant and Pulmonary Protective Potential of Fraxinus xanthoxyloides Bark Extract against CCl 4 -Induced Toxicity in Rats. Chem Biodivers 2023; 20:e202200755. [PMID: 36722706 DOI: 10.1002/cbdv.202200755] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 01/30/2023] [Accepted: 01/31/2023] [Indexed: 02/02/2023]
Abstract
Fraxinus xanthoxyloides is a perennial shrub belonging to family Oleaceae, traditionally used for malaria, jaundice, pneumonia, inflammation, and rheumatism. Our study is aimed to assess the total phenolics (TPC), flavonoids (TFC), terpenoids contents (TTC) and antioxidant profiling of F. xanthoxyloides methanol bark extract (FXBM) and its fractions, hexane, chloroform, ethyl acetate and aqueous, along with high-performance liquid chromatography with diode-array detection (HPLC-DAD). Further, the antioxidant and pulmonary protective potential was explored against carbon tetrachloride (CCl4 )-induced CCl4-induced pulmonary tissue damage in rats. The highest TPC, TFC and TTC were found in FXBM (133.29±4.19 mg/g), ethyl acetate fraction (279.55±10.35 mg/g), and chloroform fraction (0.79±0.06 mg/g), respectively. The most potent antioxidant capacity was depicted by FXBM (29.21±2.40 μg/mg) and ethyl acetate fraction (91.16±5.51 μg/mg). The HPLC-DAD analysis revealed the predominance of gallic, chlorogenic, vanillic and ferulic acid in FXBM. The administration of CCl4 induced oxidative stress, suppressed antioxidant enzymes' activities including catalase, peroxidase, superoxide dismutase, glutathione peroxidase, glutathione-S-transferase, and glutathione reductase. Further, it increased thiobarbituric acid reactive substances (TBARS) and H2 O2 levels, induced DNA injuries and reduced the total protein and glutathione content in lung tissues. The treatment of rats with FXBM restored these biochemical parameters to the normal level. Moreover, the histopathological studies of lung tissues demonstrated that FXBM protected rats' lung tissues from oxidative damage restoring normal lung functions. Thus, F. xanthoxyloides bark extract is recommended as adjuvant therapy as protective agent for patients with lung disorders.
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Affiliation(s)
- Tahira Younis
- Department of Biochemistry and Biotechnology, The Women University Multan, 60000, Multan, Pakistan
- Department of Biochemistry, Quaid-i-Azam University, 45320, Islamabad, Pakistan
| | - Faiza Jabeen
- Department of Zoology, University of Education Bank road campus, 54000, Lahore, Pakistan
| | - Ali Hussain
- Department of Zoology, University of the Punjab, 54590, Lahore, Pakistan
| | - Bilal Rasool
- Department of Zoology, Government College University, 38000, Faisalabad, Pakistan
| | - Ali Raza Ishaq
- Department of Zoology, Government College University, 38000, Faisalabad, Pakistan
| | - Atif Nawaz
- Department of Zoology, Government College University, 38000, Faisalabad, Pakistan
| | - Heba A S El-Nashar
- Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, 11566, Cairo, Egypt
| | - Mohamed El-Shazly
- Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, 11566, Cairo, Egypt
- Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, the German University in Cairo, 11835, Cairo, Egypt
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30
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Diabetes Mellitus and the Kidneys. Vet Clin North Am Small Anim Pract 2023; 53:565-580. [PMID: 36854633 DOI: 10.1016/j.cvsm.2023.01.006] [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: 02/27/2023]
Abstract
The pathomechanisms implicated in diabetic kidney disease in people are present in dogs and cats and, in theory, could lead to renal complications in companion animals with long-standing diabetes mellitus. However, these renal complications develop during a long period, and there is little to no clinical evidence that they could lead to chronic kidney disease in companion animals.
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Almazmomi MA, Alsieni M. Targeting TLR-4 Signaling to Treat COVID-19-induced Acute Kidney Injury. J Pharmacol Pharmacother 2023. [DOI: 10.1177/0976500x221147798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
The newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has turned into a potentially fatal pandemic illness. Numerous acute kidney injury (AKI) cases have been reported, although diffuse alveolar destruction and acute respiratory failure are the major symptoms of SARS-CoV-2 infection. The AKI, often known as a sudden loss of kidney function, carries a greater risk of mortality and morbidity. AKI was the second most frequent cause of death after acute respiratory distress syndrome (ARDS) in critically ill patients with coronavirus disease 2019 (COVID-19). While most patients with COVID-19 have moderate symptoms, some have severe symptoms, such as septic shock and ARDS. Also, it has been proven that some patients have severe symptoms, such as the failure of several organs. The kidneys are often affected either directly or indirectly. The major signs of kidney involvement are proteinuria and AKI. It is hypothesized that multiple mechanisms contribute to kidney injury in COVID-19. Direct infection of podocytes and proximal tubular cells in the kidneys may lead to acute tubular necrosis and collapsing glomerulopathy. SARS-CoV2 may also trigger a cascade of immunological responses that lead to AKI, including cytokine storm (CS), macrophage activation syndrome, and Toll-like receptor type-4 activation (TLR-4). Other proposed processes of AKI include interactions between organs, endothelial failure, hypercoagulability, rhabdomyolysis, and sepsis. Furthermore, ischemic damage to the kidney might result from the decreased oxygen supply. This article focuses on kidney injury’s epidemiology, etiology, and pathophysiological processes. Specifically, it focuses on the CS and the role of TLR-4 in this process. To effectively manage and treat acute kidney damage and AKI in COVID-19, it is crucial to understand the underlying molecular pathways and pathophysiology.
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Affiliation(s)
- Meaad A. Almazmomi
- Pharmaceutical Care Department, Ministry of National Guard—Health Affairs, Jeddah, Saudi Arabia
- Pharmacology Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammed Alsieni
- Pharmacology Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
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Santra D, Banerjee A, De SK, Thatoi H, Maiti S. Relation of ACE2 with co-morbidity factors in SARS-CoV-2 pathogenicity. COMPARATIVE CLINICAL PATHOLOGY 2023; 32:179-189. [PMID: 36687210 PMCID: PMC9843654 DOI: 10.1007/s00580-023-03434-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 01/01/2023] [Indexed: 01/18/2023]
Abstract
In the last 3 years of the pandemic situation, SARS-CoV-2 caused a significant number of deaths. Infection rates for symptomatic and asymptomatic patients are higher than that for death. Eventually, researchers explored that the major deaths are attributed to several comorbidity factors. The confounding factors and gender-associated infection/death rate are observed globally. This suggests that SARS-CoV-2 selects the human system recognizing the internal comorbid environment. This article explored the influences of hypertension, diabetes, cardiovascular, and renovascular disorders in COVID-19 severity and mortality. Brief mechanistic layouts have been presented here, indicating some of the comorbidity as the critical determinant in the COVID-19 pathogenesis and related mortality.
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Affiliation(s)
- Dipannita Santra
- Department of Biochemistry and Biotechnology, Cell and Molecular Therapeutics Laboratory, Oriental Institute of Science and Technology, Midnapore, India
| | - Amrita Banerjee
- Department of Biochemistry and Biotechnology, Cell and Molecular Therapeutics Laboratory, Oriental Institute of Science and Technology, Midnapore, India
| | - Subrata Kr. De
- grid.412834.80000 0000 9152 1805Department of Zoology, Vidyasagar University, Midnapore, 721102 India ,grid.411552.60000 0004 1766 4022Mahatma Gandhi University, East Midnapore, WB India
| | - Hrudayanath Thatoi
- grid.444567.00000 0004 1801 0450Department of Biotechnology, North Orissa University, Sriram Chandra Vihar, Takatpur, Baripada India
| | - Smarajit Maiti
- Department of Biochemistry and Biotechnology, Cell and Molecular Therapeutics Laboratory, Oriental Institute of Science and Technology, Midnapore, India ,Agricure Biotech Research Society, Epidemiology and Human Health Division, Midnapore, 721101 India
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Impact of COVID-19 on Uro-Oncological Patients: A Comprehensive Review of the Literature. Microorganisms 2023; 11:microorganisms11010176. [PMID: 36677468 PMCID: PMC9865028 DOI: 10.3390/microorganisms11010176] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/03/2023] [Accepted: 01/07/2023] [Indexed: 01/12/2023] Open
Abstract
Background: The aim of this paper is to discuss the impact of COVID-19 on patients with urological malignancies (prostate cancer, bladder and upper tract urothelial cancer, kidney cancer, penile and testicular cancer) and to review the available recommendations reported in the literature. Methods: A review was performed, through the PubMed database, regarding available recommendations reported in the literature, to identify studies examining the impact of COVID-19 on treatment and clinical outcomes (including upstaging, recurrence, and mortality) for uro-oncological patients. Results: The COVID-19 pandemic dramatically changed the urological guidelines and patients' access to screening programs and follow-up visits. Great efforts were undertaken to guarantee treatments to high-risk patients although follow up was not always possible due to recurrent surges, and patients with lower risk cancers had to wait for therapies. Conclusions: Physically and mentally, uro-oncological patients paid a heavy price during the COVID-19 pandemic. Long term data on the "costs" of clinical decisions made during the COVID-19 pandemic are still to be revealed and analyzed.
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Okwor CJ, Meka IA, Nto-Ezimah UA, Nto NJ, Nduka NS, Akinwande KS, Edem VF. Association of SARS-CoV-2 viral load with biochemical profile of COVID-19 patients: A nigerian experience. Niger J Clin Pract 2023; 26:109-115. [PMID: 36751832 DOI: 10.4103/njcp.njcp_1828_21] [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: 02/04/2023]
Abstract
Background Kidney involvement in coronavirus disease 2019 (COVID-19) pathology has been supported by high frequency of angiotensin-converting enzyme 2 (ACE2) expression on renal cells and reports of acute kidney injury. However, the association between host viral load and kidney function is not clear. Aim In this study, plasma levels of renal markers (urea nitrogen, creatinine, and estimated glomerular filtration rate (eGFR)) and electrolytes (sodium, potassium, chlorine, and bicarbonate) were assessed in relation to SARS-CoV-2 viral load of COVID-19 patients. Patients and Methods This cross-sectional study involved 144 consenting COVID-19 patients admitted to the Ogun state COVID-19 isolation center between May and December 2020. All participants presented with mild respiratory symptoms and did not require ICU admission or ventilation support. Data included reverse transcriptase polymerase chain reaction (RT-PCR) cycle threshold (CT) value, blood urea nitrogen (BUN), creatinine, sodium, potassium, chlorine, bicarbonate measurements, and glomerular filtration rate. Reference intervals were used as comparators, and multiple linear regression model was fitted. Statistical significance was set at P < 0.05. Results BUN level and creatinine were elevated in 4 (2.8%) and 42 (29.2%) patients, respectively, with lowered eGFR observed in 37 (25.7%) patients. Hyponatremia and hypokalemia were observed in 35 (24.3%) and 21 (14.6%) patients, respectively, while hypochloremia was observed in 21 (14.6%) patients. Lowered bicarbonate was observed in 29 (20.1%) patients. Linear regression showed statistically significant association (R2 = 0.340, P = 0.032) between RT-PCR CT value and eGFR (β = 0.006, P = 0.017) as well as HCO3 (β = -0.262, P = 0.036). Conclusion COVID-19 patients with mild respiratory symptoms exhibited renal abnormalities, electrolytes, and acid-base imbalances which were partly associated with SARS-CoV-2 viral load.
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Affiliation(s)
- C J Okwor
- Department of Chemical Pathology, College of Medicine, University of Nigeria/University of Nigeria Teaching Hospital, Ituku/Ozalla, Nigeria
| | - I A Meka
- Department of Chemical Pathology, College of Medicine, University of Nigeria/University of Nigeria Teaching Hospital, Ituku/Ozalla, Nigeria
| | - U A Nto-Ezimah
- Department of Chemical Pathology, College of Medicine, University of Nigeria/University of Nigeria Teaching Hospital, Ituku/Ozalla, Nigeria
| | - N J Nto
- Department of Anatomy, University of Nigeria, Enugu Campus, Nigeria
| | - N S Nduka
- 54gene Biotechnology, Lagos, Nigeria
| | - K S Akinwande
- Department of Chemical Pathology and Immunology, Federal Medical Center, Abeokuta, Nigeria
| | - V F Edem
- Department of Immunology, University of Ibadan, Ibadan, Nigeria
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35
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Zhang W, Liu L, Xiao X, Zhou H, Peng Z, Wang W, Huang L, Xie Y, Xu H, Tao L, Nie W, Yuan X, Liu F, Yuan Q. Identification of common molecular signatures of SARS-CoV-2 infection and its influence on acute kidney injury and chronic kidney disease. Front Immunol 2023; 14:961642. [PMID: 37026010 PMCID: PMC10070855 DOI: 10.3389/fimmu.2023.961642] [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] [Received: 06/05/2022] [Accepted: 03/07/2023] [Indexed: 04/08/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the main cause of COVID-19, causing hundreds of millions of confirmed cases and more than 18.2 million deaths worldwide. Acute kidney injury (AKI) is a common complication of COVID-19 that leads to an increase in mortality, especially in intensive care unit (ICU) settings, and chronic kidney disease (CKD) is a high risk factor for COVID-19 and its related mortality. However, the underlying molecular mechanisms among AKI, CKD, and COVID-19 are unclear. Therefore, transcriptome analysis was performed to examine common pathways and molecular biomarkers for AKI, CKD, and COVID-19 in an attempt to understand the association of SARS-CoV-2 infection with AKI and CKD. Three RNA-seq datasets (GSE147507, GSE1563, and GSE66494) from the GEO database were used to detect differentially expressed genes (DEGs) for COVID-19 with AKI and CKD to search for shared pathways and candidate targets. A total of 17 common DEGs were confirmed, and their biological functions and signaling pathways were characterized by enrichment analysis. MAPK signaling, the structural pathway of interleukin 1 (IL-1), and the Toll-like receptor pathway appear to be involved in the occurrence of these diseases. Hub genes identified from the protein-protein interaction (PPI) network, including DUSP6, BHLHE40, RASGRP1, and TAB2, are potential therapeutic targets in COVID-19 with AKI and CKD. Common genes and pathways may play pathogenic roles in these three diseases mainly through the activation of immune inflammation. Networks of transcription factor (TF)-gene, miRNA-gene, and gene-disease interactions from the datasets were also constructed, and key gene regulators influencing the progression of these three diseases were further identified among the DEGs. Moreover, new drug targets were predicted based on these common DEGs, and molecular docking and molecular dynamics (MD) simulations were performed. Finally, a diagnostic model of COVID-19 was established based on these common DEGs. Taken together, the molecular and signaling pathways identified in this study may be related to the mechanisms by which SARS-CoV-2 infection affects renal function. These findings are significant for the effective treatment of COVID-19 in patients with kidney diseases.
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Affiliation(s)
- Weiwei Zhang
- Department of Nephrology, Xiangya Hospital of Central South University, Changsha, China
| | - Leping Liu
- Department of Pediatrics, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Xiangcheng Xiao
- Department of Nephrology, Xiangya Hospital of Central South University, Changsha, China
| | - Hongshan Zhou
- Department of Nephrology, Xiangya Hospital of Central South University, Changsha, China
| | - Zhangzhe Peng
- Department of Nephrology, Xiangya Hospital of Central South University, Changsha, China
- Organ Fibrosis Key Lab of Hunan Province, Central South University, Changsha, China
| | - Wei Wang
- Department of Nephrology, Xiangya Hospital of Central South University, Changsha, China
- Organ Fibrosis Key Lab of Hunan Province, Central South University, Changsha, China
| | - Ling Huang
- Department of Nephrology, Xiangya Hospital of Central South University, Changsha, China
- Organ Fibrosis Key Lab of Hunan Province, Central South University, Changsha, China
| | - Yanyun Xie
- Department of Nephrology, Xiangya Hospital of Central South University, Changsha, China
- Organ Fibrosis Key Lab of Hunan Province, Central South University, Changsha, China
| | - Hui Xu
- Department of Nephrology, Xiangya Hospital of Central South University, Changsha, China
- Organ Fibrosis Key Lab of Hunan Province, Central South University, Changsha, China
| | - Lijian Tao
- Department of Nephrology, Xiangya Hospital of Central South University, Changsha, China
- Organ Fibrosis Key Lab of Hunan Province, Central South University, Changsha, China
| | - Wannian Nie
- Department of Nephrology, Xiangya Hospital of Central South University, Changsha, China
| | - Xiangning Yuan
- Department of Nephrology, Xiangya Hospital of Central South University, Changsha, China
- Organ Fibrosis Key Lab of Hunan Province, Central South University, Changsha, China
| | - Fang Liu
- Health Management Center, Xiangya Hospital of Central South University, Changsha, China
- *Correspondence: Fang Liu, ; Qiongjing Yuan,
| | - Qiongjing Yuan
- Department of Nephrology, Xiangya Hospital of Central South University, Changsha, China
- Organ Fibrosis Key Lab of Hunan Province, Central South University, Changsha, China
- National Clinical Medical Research Center for Geriatric Diseases, Xiangya Hospital of Central South University, Changsha, China
- Research Center for Medical Metabolomics, Xiangya Hospital of Central South University, Changsha, China
- *Correspondence: Fang Liu, ; Qiongjing Yuan,
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Nelson JW, Ortiz-Melo DI, Mattocks NK, Emathinger JM, Prescott J, Xu K, Griffiths RC, Wakasaki R, Piehowski PD, Hutchens MP, Coffman TM, Gurley SB. Soluble ACE2 Is Filtered into the Urine. KIDNEY360 2022; 3:2086-2094. [PMID: 36591353 PMCID: PMC9802553 DOI: 10.34067/kid.0001622022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 08/01/2022] [Indexed: 02/01/2023]
Abstract
Background ACE2 is a key enzyme in the renin-angiotensin system (RAS) capable of balancing the RAS by metabolizing angiotensin II (AngII). First described in cardiac tissue, abundance of ACE2 is highest in the kidney, and it is also expressed in several extrarenal tissues. Previously, we reported an association between enhanced susceptibility to hypertension and elevated renal AngII levels in global ACE2-knockout mice. Methods To examine the effect of ACE2 expressed in the kidney, relative to extrarenal expression, on the development of hypertension, we used a kidney crosstransplantation strategy with ACE2-KO and WT mice. In this model, both native kidneys are removed and renal function is provided entirely by the transplanted kidney, such that four experimental groups with restricted ACE2 expression are generated: WT→WT (WT), KO→WT (KidneyKO), WT→KO (SystemicKO), and KO→KO (TotalKO). Additionally, we used nanoscale mass spectrometry-based proteomics to identify ACE2 fragments in early glomerular filtrate of mice. Results Although significant differences in BP were not detected, a major finding of our study is that shed or soluble ACE2 (sACE2) was present in urine of KidneyKO mice that lack renal ACE2 expression. Detection of sACE2 in the urine of KidneyKO mice during AngII-mediated hypertension suggests that sACE2 originating from extrarenal tissues can reach the kidney and be excreted in urine. To confirm glomerular filtration of ACE2, we used micropuncture and nanoscale proteomics to detect peptides derived from ACE2 in the Bowman's space. Conclusions Our findings suggest that both systemic and renal tissues may contribute to sACE2 in urine, identifying the kidney as a major site for ACE2 actions. Moreover, filtration of sACE2 into the lumen of the nephron may contribute to the pathophysiology of kidney diseases characterized by disruption of the glomerular filtration barrier.
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Affiliation(s)
- Jonathan W. Nelson
- Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon
| | - David I. Ortiz-Melo
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina
| | - Natalie K. Mattocks
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina
| | - Jacqueline M. Emathinger
- Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon
| | - Jessica Prescott
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina
| | - Katherine Xu
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina
| | - Robert C. Griffiths
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina
| | - Rumie Wakasaki
- Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, Oregon
| | - Paul D. Piehowski
- Environmental and Biological Services Division, Pacific Northwest National Laboratory, Richland, Washington
| | - Michael P. Hutchens
- Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, Oregon
| | - Thomas M. Coffman
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina
- Program in Cardiovascular and Metabolic Disorders, Duke–NUS Medical School, Singapore
| | - Susan B. Gurley
- Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina
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Wysocki J, Batlle D. ACE2 in the Urine: Where Does It Come From? KIDNEY360 2022; 3:2001-2004. [PMID: 36591363 PMCID: PMC9802542 DOI: 10.34067/kid.0005592022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 10/14/2022] [Indexed: 01/01/2023]
Affiliation(s)
- Jan Wysocki
- Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Daniel Batlle
- Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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Khattab ESAEH, Ragab A, Abol-Ftouh MA, Elhenawy AA. Therapeutic strategies for Covid-19 based on molecular docking and dynamic studies to the ACE-2 receptors, Furin, and viral spike proteins. J Biomol Struct Dyn 2022; 40:13291-13309. [PMID: 34647855 PMCID: PMC8544674 DOI: 10.1080/07391102.2021.1989036] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
SARS-CoV-2 is a pandemic virus that caused infections and deaths in many world countries, including the Middle East. The virus-infected human cells by binding via ACE-2 receptor through the Spike protein of the virus with Furin's help causing cell membrane fusion leading to Covid-19-cell entry. No registered drugs or vaccines are triggering this pandemic viral disease yet. Our present work is based on molecular docking and dynamics simulation that performed to spike protein-ACE-2 interface complex, ACE-2 receptor, Spike protein (RBD), and Furin as targets for new small molecules. These drugs target new potential therapies to show their probabilities toward the active sites of mentioned proteins, strongly causing inhibition and/or potential therapy for covid-19. All target proteins were estimated against new target compounds under clinical trials and repurposing drugs currently present. Possibilities of those molecules and potential therapeutics acting on a certain target were predicted. MD simulations over 200 ns with molecular mechanics-generalized Born surface area (MMGBSA) binding energy calculations were performed. The structural and energetic analyses demonstrated the stability of the ligands-MPros complex. Our present work will introduce new visions of some biologically active molecules for further studies in-vitro and in-vivo for Covid-19, repurposing of these molecules should be taking place under clinical works and offering different strategies for drugs repurposing against Covid-19 diseases.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
| | - Ahmed Ragab
- Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City, Cairo, Egypt,CONTACT Ahmed Ragab ; Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City, Cairo11884, Egypt
| | - Mahmoud A. Abol-Ftouh
- Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City, Cairo, Egypt,Mahmoud A. Abol-Ftouh Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City, Cairo11884, Egypt
| | - Ahmed A. Elhenawy
- Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City, Cairo, Egypt
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Temiz MZ, Hacibey I, Yazar RO, Sevdi MS, Kucuk SH, Alkurt G, Doganay L, Dinler Doganay G, Dincer MM, Yuruk E, Erkalp K, Muslumanoglu AY. Altered kidney function induced by SARS-CoV-2 infection and acute kidney damage markers predict survival outcomes of COVID-19 patients: a prospective pilot study. Ren Fail 2022; 44:233-240. [PMID: 35172674 PMCID: PMC8856025 DOI: 10.1080/0886022x.2022.2032743] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 01/10/2022] [Accepted: 01/10/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Literature with regard to coronavirus disease 2019 (COVID-19) associated morbidities and the risk factors for death are still emerging. In this study, we investigated the presence of kidney damage markers and their predictive value for survival among hospitalized subjects with COVID-19. METHODS Forty-seven participants was included and grouped as: 'COVID-19 patients before treatment', 'COVID-19 patients after treatment', 'COVID-19 patients under treatment in intensive care unit (ICU)', and 'controls'. Kidney function tests and several kidney injury biomarkers were compared between the groups. Cumulative rates of death from COVID-19 were determined using the Kaplan-Meier method. The associations between covariates including kidney injury markers and death from COVID-19 were examined, as well. RESULTS Serum creatinine and cystatin C levels, urine Kidney Injury Molecule-1 (KIM-1)/creatinine ratio, and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), CKD-EPI cystatin C, and CKD-EPI creatinine-cystatin C levels demonstrated significant difference among the groups. The most significant difference was noted between the groups 'COVID-19 patients before treatment' and 'COVID-19 patients under treatment in ICU'. Advancing age, proteinuria, elevated serum cystatin C, and urine KIM-1/creatinine ratio were all significant univariate correlates of death (p < 0.05, for all). However, only elevated urine KIM-1/creatinine ratio retained significance in an age, sex, and comorbidities adjusted multivariable Cox regression (OR 6.11; 95% CI: 1.22-30.53; p = 0.02), whereas serum cystatin C showing only a statistically non-significant trend (OR 1.42; 95% CI: 0.00-2.52; p = 0.09). CONCLUSIONS Our findings clearly demonstrated the acute kidney injury related to COVID-19. Moreover, urine KIM-1/creatinine ratio was associated with COVID-19 specific death.
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Affiliation(s)
- Mustafa Zafer Temiz
- Department of Urology, Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Ibrahim Hacibey
- Department of Urology, Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Ramazan Omer Yazar
- Department of Urology, Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Mehmet Salih Sevdi
- Department of Anesthesiology and Reanimation, Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Suat Hayri Kucuk
- Department of Biochemistry, Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Gizem Alkurt
- Genomic Laboratory (GLAB), Umraniye Training and Research Hospital, Elmalikent, Istanbul, Turkey
| | - Levent Doganay
- Genomic Laboratory (GLAB), Umraniye Training and Research Hospital, Elmalikent, Istanbul, Turkey
| | - Gizem Dinler Doganay
- Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul, Turkey
| | | | - Emrah Yuruk
- Department of Urology, BHT Clinic Istanbul Tema Hospital, Istanbul, Turkey
| | - Kerem Erkalp
- Department of Anesthesiology and Reanimation, Bagcilar Training and Research Hospital, Istanbul, Turkey
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dos Santos AAC, Rodrigues LE, Alecrim-Zeza AL, de Araújo Ferreira L, Trettel CDS, Gimenes GM, da Silva AF, Sousa-Filho CPB, Serdan TDA, Levada-Pires AC, Hatanaka E, Borges FT, de Barros MP, Cury-Boaventura MF, Bertolini GL, Cassolla P, Marzuca-Nassr GN, Vitzel KF, Pithon-Curi TC, Masi LN, Curi R, Gorjao R, Hirabara SM. Molecular and cellular mechanisms involved in tissue-specific metabolic modulation by SARS-CoV-2. Front Microbiol 2022; 13:1037467. [PMID: 36439786 PMCID: PMC9684198 DOI: 10.3389/fmicb.2022.1037467] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 10/26/2022] [Indexed: 09/09/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is triggered by the SARS-CoV-2, which is able to infect and cause dysfunction not only in lungs, but also in multiple organs, including central nervous system, skeletal muscle, kidneys, heart, liver, and intestine. Several metabolic disturbances are associated with cell damage or tissue injury, but the mechanisms involved are not yet fully elucidated. Some potential mechanisms involved in the COVID-19-induced tissue dysfunction are proposed, such as: (a) High expression and levels of proinflammatory cytokines, including TNF-α IL-6, IL-1β, INF-α and INF-β, increasing the systemic and tissue inflammatory state; (b) Induction of oxidative stress due to redox imbalance, resulting in cell injury or death induced by elevated production of reactive oxygen species; and (c) Deregulation of the renin-angiotensin-aldosterone system, exacerbating the inflammatory and oxidative stress responses. In this review, we discuss the main metabolic disturbances observed in different target tissues of SARS-CoV-2 and the potential mechanisms involved in these changes associated with the tissue dysfunction.
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Affiliation(s)
| | - Luiz Eduardo Rodrigues
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Amanda Lins Alecrim-Zeza
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Liliane de Araújo Ferreira
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Caio dos Santos Trettel
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Gabriela Mandú Gimenes
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Adelson Fernandes da Silva
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | | | - Tamires Duarte Afonso Serdan
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
- Department of Molecular Pathobiology, University of New York, New York, NY, United States
| | - Adriana Cristina Levada-Pires
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Elaine Hatanaka
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Fernanda Teixeira Borges
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
- Divisão de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Marcelo Paes de Barros
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Maria Fernanda Cury-Boaventura
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Gisele Lopes Bertolini
- Department of Physiological Sciences, Biological Science Center, State University of Londrina, Londrina, PR, Brazil
| | - Priscila Cassolla
- Department of Physiological Sciences, Biological Science Center, State University of Londrina, Londrina, PR, Brazil
| | | | - Kaio Fernando Vitzel
- School of Health Sciences, College of Health, Massey University, Auckland, New Zealand
| | - Tania Cristina Pithon-Curi
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Laureane Nunes Masi
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Rui Curi
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
- Instituto Butantan, São Paulo, Brazil
| | - Renata Gorjao
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Sandro Massao Hirabara
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
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Vergara A, Wang K, Colombo D, Gheblawi M, Rasmuson J, Mandal R, Del Nonno F, Chiu B, Scholey JW, Soler MJ, Wishart DS, Oudit GY. Urinary angiotensin-converting enzyme 2 and metabolomics in COVID-19-mediated kidney injury. Clin Kidney J 2022; 16:272-284. [PMID: 36751625 PMCID: PMC9494506 DOI: 10.1093/ckj/sfac215] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Indexed: 11/13/2022] Open
Abstract
Background Angiotensin-converting enzyme 2 (ACE2), the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is highly expressed in the kidneys. Beyond serving as a crucial endogenous regulator of the renin-angiotensin system, ACE2 also possess a unique function to facilitate amino acid absorption. Our observational study sought to explore the relationship between urine ACE2 (uACE2) and renal outcomes in coronavirus disease 2019 (COVID-19). Methods In a cohort of 104 patients with COVID-19 without acute kidney injury (AKI), 43 patients with COVID-19-mediated AKI and 36 non-COVID-19 controls, we measured uACE2, urine tumour necrosis factor receptors I and II (uTNF-RI and uTNF-RII) and neutrophil gelatinase-associated lipocalin (uNGAL). We also assessed ACE2 staining in autopsy kidney samples and generated a propensity score-matched subgroup of patients to perform a targeted urine metabolomic study to describe the characteristic signature of COVID-19. Results uACE2 is increased in patients with COVID-19 and further increased in those that developed AKI. After adjusting uACE2 levels for age, sex and previous comorbidities, increased uACE2 was independently associated with a >3-fold higher risk of developing AKI [odds ratio 3.05 (95% confidence interval 1.23‒7.58), P = .017]. Increased uACE2 corresponded to a tubular loss of ACE2 in kidney sections and strongly correlated with uTNF-RI and uTNF-RII. Urine quantitative metabolome analysis revealed an increased excretion of essential amino acids in patients with COVID-19, including leucine, isoleucine, tryptophan and phenylalanine. Additionally, a strong correlation was observed between urine amino acids and uACE2. Conclusions Elevated uACE2 is related to AKI in patients with COVID-19. The loss of tubular ACE2 during SARS-CoV-2 infection demonstrates a potential link between aminoaciduria and proximal tubular injury.
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Affiliation(s)
- Ander Vergara
- Department of Medicine, Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada,Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Kaiming Wang
- Department of Medicine, Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada,Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Daniele Colombo
- Department of Pathology, National Institute for Infectious Diseases “Lazzaro Spallanzani,” IRCCS, Rome, Italy
| | - Mahmoud Gheblawi
- Department of Medicine, Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada,Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Jaslyn Rasmuson
- Department of Medicine, Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada,Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Rupasri Mandal
- Metabolomics Innovation Center, University of Alberta, Edmonton, Alberta, Canada
| | - Franca Del Nonno
- Department of Pathology, National Institute for Infectious Diseases “Lazzaro Spallanzani,” IRCCS, Rome, Italy
| | - Brian Chiu
- Department of Laboratory Medicine and Pathology, University of Alberta Hospital, Edmonton, Alberta, Canada
| | - James W Scholey
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada
| | - María José Soler
- Department of Nephrology, Vall d’Hebron University Hospital, Barcelona, Spain,Nephrology and Transplantation Research Group, Vall d’Hebron Research Institute, Barcelona, Spain
| | - David S Wishart
- Metabolomics Innovation Center, University of Alberta, Edmonton, Alberta, Canada
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Sen R, Sengupta D, Mukherjee A. Mechanical dependency of the SARS-CoV-2 virus and the renin-angiotensin-aldosterone (RAAS) axis: a possible new threat. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:62235-62247. [PMID: 34859345 PMCID: PMC8638800 DOI: 10.1007/s11356-021-16356-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 09/01/2021] [Indexed: 04/12/2023]
Abstract
Pathogens in our environment can act as agents capable of inflicting severe human diseases. Among them, the SARS-CoV-2 virus has recently plagued the globe and paralyzed the functioning of ordinary human life. The virus enters the cell through the angiotensin-converting enzyme-2 (ACE-2) receptor, an integral part of the renin-angiotensin system (RAAS). Reports on hypertension and its relation to the modulation of the RAAS are generating interest in the scientific community. This short review focuses on the SARS-CoV-2 infection's direct and indirect effects on our body through modulation of the RAAS axis. A patient having severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, which causes COVID-19 relates to hypertension as a pre-existing disease or develops it in a post-COVID scenario. Several studies on how SARS-CoV-2 modulates the RAAS axis indicate that it alters our body's physiological balance. This review seeks to establish a hypothesis on the mechanical dependency of SARS-CoV-2 and RAAS modulation in the human body. This study intends to impart ideas on drug development and designing by targeting the modulation of the RAAS axis to inactivate the pathogenicity of the SARS-CoV-2 virus. A systematic hypothesis can severely attenuate the pathogenicity of the dreadful viruses of the future.
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Affiliation(s)
- Rohit Sen
- Department of Zoology, Charuchandra College, University of Calcutta, 22, Lake Road, Kolkata, 700029 India
| | | | - Avinaba Mukherjee
- Department of Zoology, Charuchandra College, University of Calcutta, 22, Lake Road, Kolkata, 700029 India
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Early reduction of estimated Glomerular Filtration Rate (eGFR) predicts poor outcome in acutely ill hospitalized COVID-19 patients firstly admitted to medical regular wards (eGFR-COV19 study). Biomed Pharmacother 2022; 153:113454. [PMID: 36076568 PMCID: PMC9300590 DOI: 10.1016/j.biopha.2022.113454] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/13/2022] [Accepted: 07/19/2022] [Indexed: 01/08/2023] Open
Abstract
Background Methods Results Conclusions
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Gnanenthiran SR, Borghi C, Burger D, Caramelli B, Charchar F, Chirinos JA, Cohen JB, Cremer A, Di Tanna GL, Duvignaud A, Freilich D, Gommans DHF, Gracia-Ramos AE, Murray TA, Pelorosso F, Poulter NR, Puskarich MA, Rizas KD, Rothlin R, Schlaich MP, Schreinlecher M, Steckelings UM, Sharma A, Stergiou GS, Tignanelli CJ, Tomaszewski M, Unger T, van Kimmenade RRJ, Wainford RD, Williams B, Rodgers A, Schutte AE. Renin-Angiotensin System Inhibitors in Patients With COVID-19: A Meta-Analysis of Randomized Controlled Trials Led by the International Society of Hypertension. J Am Heart Assoc 2022; 11:e026143. [PMID: 36000426 PMCID: PMC9496439 DOI: 10.1161/jaha.122.026143] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Background Published randomized controlled trials are underpowered for binary clinical end points to assess the safety and efficacy of renin‐angiotensin system inhibitors (RASi) in adults with COVID‐19. We therefore performed a meta‐analysis to assess the safety and efficacy of RASi in adults with COVID‐19. Methods and Results MEDLINE, EMBASE, ClinicalTrials.gov, and the Cochrane Controlled Trial Register were searched for randomized controlled trials that randomly assigned patients with COVID‐19 to RASi continuation/commencement versus no RASi therapy. The primary outcome was all‐cause mortality at ≤30 days. A total of 14 randomized controlled trials met the inclusion criteria and enrolled 1838 participants (aged 59 years, 58% men, mean follow‐up 26 days). Of the trials, 11 contributed data. We found no effect of RASi versus control on all‐cause mortality (7.2% versus 7.5%; relative risk [RR], 0.95; [95% CI, 0.69–1.30]) either overall or in subgroups defined by COVID‐19 severity or trial type. Network meta‐analysis identified no difference between angiotensin‐converting enzyme inhibitors versus angiotensin II receptor blockers. RASi users had a nonsignificant reduction in acute myocardial infarction (2.1% versus 3.6%; RR, 0.59; [95% CI, 0.33–1.06]), but increased risk of acute kidney injury (7.0% versus 3.6%; RR, 1.82; [95% CI, 1.05–3.16]), in trials that initiated and continued RASi. There was no increase in need for dialysis or differences in congestive cardiac failure, cerebrovascular events, venous thromboembolism, hospitalization, intensive care admission, inotropes, or mechanical ventilation. Conclusions This meta‐analysis of randomized controlled trials evaluating angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers versus control in patients with COVID‐19 found no difference in all‐cause mortality, a borderline decrease in myocardial infarction, and an increased risk of acute kidney injury with RASi. Our findings provide strong evidence that RASi can be used safely in patients with COVID‐19.
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Affiliation(s)
- Sonali R Gnanenthiran
- The George Institute for Global Health University of New South Wales Sydney NSW Australia
| | - Claudio Borghi
- Department of Medical and Surgical Sciences University of Bologna Italy
| | - Dylan Burger
- Department of Cellular and Molecular Medicine, Kidney Research Centre, Ottawa Hospital Research Institute University of Ottawa Canada
| | - Bruno Caramelli
- Interdisciplinary Medicine in Cardiology Unit, InCor University of Sao Paulo Brazil
| | - Fadi Charchar
- School of Health and Life Sciences Federation University Australia Ballarat VIC Australia
| | - Julio A Chirinos
- Division of Cardiovascular Medicine University of Pennsylvania Perelman School of Medicine Philadelphia PA
| | - Jordana B Cohen
- Renal-Electrolyte and Hypertension Division and Department of Biostatistics, Epidemiology, and Informatics University of Pennsylvania Perelman School of Medicine Philadelphia PA
| | - Antoine Cremer
- Department of Cardiology and Hypertension, Hypertension Excellence Center Hôpital Saint André, Centre Hospitalier Universitaire de Bordeaux & University Bordeaux Bordeaux France
| | - Gian Luca Di Tanna
- The George Institute for Global Health University of New South Wales Sydney NSW Australia
| | - Alexandre Duvignaud
- Department of Infectious Diseases and Tropical Medicine, Division of Tropical Medicine and Clinical International Health Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux & University Bordeaux Bordeaux France
| | | | - D H Frank Gommans
- Department of Cardiology Radboud University Medical Center Nijmegen The Netherlands.,Netherlands Heart Institute Utrecht The Netherlands
| | - Abraham E Gracia-Ramos
- Departamento de Medicina Interna, Hospital General, Centro Médico Nacional "La Raza" Instituto Mexicano del Seguro Social Mexico City Mexico.,Departamento de Medicina Interna Hospital Regional de Alta Especialidad de Zumpango Estado de Mexico Mexico
| | - Thomas A Murray
- Division of Biostatistics, School of Public Health University of Minnesota Minneapolis MN
| | - Facundo Pelorosso
- Asociacion Argentina de Medicamentos Ciudad Autonoma de Buenos Aires Argentina.,Servicio de Anatomía Patologica, Hospital de Alta Complejidad El Calafate SAMIC Santa Cruz Argentina
| | - Neil R Poulter
- Imperial Clinical Trials Unit Imperial College London London UK
| | - Michael A Puskarich
- Department of Emergency Medicine Hennepin County Medical Center University of Minnesota Minneapolis MN
| | - Konstantinos D Rizas
- Medizinische Klinik und Poliklinik I Ludwig Maximilian University Hospital Munich Munich Germany
| | - Rodolfo Rothlin
- Asociacion Argentina de Medicamentos Ciudad Autonoma de Buenos Aires Argentina.,Sociedad Argentina de Farmacología Clínica, Asociacion Medica Argentina Buenos Aires Argentina
| | - Markus P Schlaich
- Dobney Hypertension Centre, Medical School, Royal Perth Hospital Unit-Royal Perth Hospital Medical Research Foundation University of Western Australia Perth Australia
| | - Michael Schreinlecher
- Department of Internal Medicine III, Cardiology and Angiology Medical University of Innsbruck Innsbruck Austria
| | | | - Abhinav Sharma
- Division of Cardiology McGill University Health Centre Montreal Quebec Canada
| | - George S Stergiou
- Hypertension Center STRIDE-7, School of Medicine, Third Department of Medicine, Sotiria Hospital National and Kapodistrian University of Athens Athens Greece
| | | | - Maciej Tomaszewski
- Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health University of Manchester Manchester UK.,Manchester Academic Health Science Centre Manchester University National Health Service Foundation Trust Manchester Manchester UK
| | - Thomas Unger
- Cardiovascular Research Institute Maastricht-School for Cardiovascular Diseases Maastricht University Maastricht The Netherlands
| | - Roland R J van Kimmenade
- Department of Cardiology Radboud University Medical Center Nijmegen The Netherlands.,Netherlands Heart Institute Utrecht The Netherlands
| | - Richard D Wainford
- Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute Boston University School of Medicine Boston MA
| | - Bryan Williams
- Institute of Cardiovascular Science University College London and National Institute for Health Research University College London Hospitals Biomedical Research Centre London UK
| | - Anthony Rodgers
- The George Institute for Global Health University of New South Wales Sydney NSW Australia
| | - Aletta E Schutte
- The George Institute for Global Health University of New South Wales Sydney NSW Australia
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Babu G, Nobel FA. Identification of differentially expressed genes and their major pathways among the patient with COVID-19, cystic fibrosis, and chronic kidney disease. INFORMATICS IN MEDICINE UNLOCKED 2022; 32:101038. [PMID: 35966126 PMCID: PMC9357445 DOI: 10.1016/j.imu.2022.101038] [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: 06/04/2022] [Revised: 07/31/2022] [Accepted: 08/01/2022] [Indexed: 11/19/2022] Open
Abstract
The SARS-CoV-2 virus causes Coronavirus disease, an infectious disease. The majority of people who are infected with this virus will have mild to moderate respiratory symptoms. Multiple studies have proved that there is a substantial pathophysiological link between COVID-19 disease and patients having comorbidities such as cystic fibrosis and chronic kidney disease. In this study, we attempted to identify differentially expressed genes as well as genes that intersected among them in order to comprehend their compatibility. Gene expression profiling indicated that 849 genes were mutually exclusive and functional analysis was done within the context of gene ontology and key pathways involvement. Three genes (PRPF31, FOXN2, and RIOK3) were commonly upregulated in the analysed datasets of three disease categories. These genes could be potential biomarkers for patients with COVID-19 and cystic fibrosis, and COVID-19 and chronic kidney disease. Further extensive analyses have been performed to describe how these genes are regulated by various transcription factors and microRNAs. Then, our analyses revealed six hub genes (PRPF31, FOXN2, RIOK3, UBC, HNF4A, and ELAVL). As they were involved in the interaction between COVID-19 and the patient with CF and CKD, they could help researchers identify potential therapeutic molecules. Some drugs have been predicted based on the upregulated genes, which may have a significant impact on reducing the burden of these diseases in the future.
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Affiliation(s)
- Golap Babu
- Department of Biochemistry and Molecular Biology, Jahangirnagar University, Savar, Dhaka, 1342, Bangladesh
| | - Fahim Alam Nobel
- Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Santosh, Tangail, 1902, Bangladesh
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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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Nguyen BQ, Alaimo DJ. Glossopharyngeal Neuralgia Secondary to COVID-19: A Case Report. Cureus 2022; 14:e26817. [PMID: 35971353 PMCID: PMC9372386 DOI: 10.7759/cureus.26817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2022] [Indexed: 11/18/2022] Open
Abstract
Glossopharyngeal neuralgia (GPN) is a painful condition characterized by stabbing pain throughout the glossopharyngeal nerve distribution. Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, we have learned that COVID-19 may induce neurological symptoms and complications. This case report presents a 54-year-old patient diagnosed with GPN, potentially secondary to COVID-19. The pain resolved spontaneously in three months without the need for medication. We discuss our diagnostic approach for this patient and propose a possible theory about the relation between cranial neuralgias and COVID-19.
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48
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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: 30] [Impact Index Per Article: 10.0] [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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49
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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: 34] [Impact Index Per Article: 11.3] [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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50
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Sultan RH, Abdallah M, Ali TM, Ahmed AE, Assal HH, Elesawy BH, Ahmed OM. The Associations between Cytokine Levels, Kidney and Heart Function Biomarkers, and Expression Levels of Angiotensin-Converting Enzyme-2 and Neuropilin-1 in COVID-19 Patients. Vaccines (Basel) 2022; 10:1045. [PMID: 35891209 PMCID: PMC9316107 DOI: 10.3390/vaccines10071045] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/20/2022] [Accepted: 06/22/2022] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Higher expression of angiotensin-converting enzyme-2 (ACE-2) in addition to neuropilin-1 (NRP-1) can lead to a cytokine storm which is correlated to higher mortality rate and contributes to the progression of renal diseases and the pathogenesis of coronary heart disease (CHD) in COVID-19 patients. AIM We herein sought to examine correlations between cytokine levels, ACE-2 and NRP-1 expression, renal function biomarkers, and cardiac enzymes in COVID-19 patients. PATIENTS AND METHODS For the study, 50 healthy subjects and 100 COVID-19 patients were enrolled. Then, confirmed cases of COVID-19 were divided into two groups-those with moderate infection and those with severe infection-and compared to healthy controls. Serum creatinine, urea, CK-MB, LDH, troponin I, IL-1β, IL-4, IL-10, IL-17, and INF-γ levels were estimated. We also studied the gene expression for ACE-2 and NRP-1 in blood samples utilizing quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS All COVID-19 patients demonstrated a significant increase in the levels of serum creatinine, urea, CK-MB, LDH, and troponin I, as well as examined cytokines compared to the healthy controls. Furthermore, ACE-2 mRNA and NRP-1 mRNA expression levels demonstrated a significant increase in both severe and moderate COVID-19 patient groups. In the severe group, serum creatinine and urea levels were positively correlated with IL-10, INF-γ, NRP-1, and ACE-2 expression levels. Moreover, LDH was positively correlated with all the examined cytokine, NRP-1, and ACE-2 expression levels. CONCLUSION Deficits in renal and cardiac functions might be attributable to cytokine storm resulting from the higher expression of ACE-2 and NRP-1 in cases of COVID-19.
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Affiliation(s)
- Rabab Hussain Sultan
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences, Beni-Suef University, Beni-Suef 62521, Egypt;
| | - Maged Abdallah
- Department of Anesthesia and Intensive Care, Faculty of Medicine, Cairo University, Cairo 11562, Egypt;
| | - Tarek M. Ali
- Department of Physiology, College of Medicine, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;
| | - Amr E. Ahmed
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences, Beni-Suef University, Beni-Suef 62521, Egypt;
| | - Hebatallah Hany Assal
- Department of Chest Medicine, Faculty of Medicine, Cairo University, Cairo 11562, Egypt;
| | - Basem H. Elesawy
- Department of Pathology, College of Medicine, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;
| | - Osama M. Ahmed
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef 62521, Egypt;
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