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Kotton CN, Kamar N, Wojciechowski D, Eder M, Hopfer H, Randhawa P, Sester M, Comoli P, Tedesco Silva H, Knoll G, Brennan DC, Trofe-Clark J, Pape L, Axelrod D, Kiberd B, Wong G, Hirsch HH. The Second International Consensus Guidelines on the Management of BK Polyomavirus in Kidney Transplantation. Transplantation 2024; 108:1834-1866. [PMID: 38605438 PMCID: PMC11335089 DOI: 10.1097/tp.0000000000004976] [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: 10/26/2023] [Revised: 01/10/2024] [Accepted: 01/18/2024] [Indexed: 04/13/2024]
Abstract
BK polyomavirus (BKPyV) remains a significant challenge after kidney transplantation. International experts reviewed current evidence and updated recommendations according to Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Risk factors for BKPyV-DNAemia and biopsy-proven BKPyV-nephropathy include recipient older age, male sex, donor BKPyV-viruria, BKPyV-seropositive donor/-seronegative recipient, tacrolimus, acute rejection, and higher steroid exposure. To facilitate early intervention with limited allograft damage, all kidney transplant recipients should be screened monthly for plasma BKPyV-DNAemia loads until month 9, then every 3 mo until 2 y posttransplant (3 y for children). In resource-limited settings, urine cytology screening at similar time points can exclude BKPyV-nephropathy, and testing for plasma BKPyV-DNAemia when decoy cells are detectable. For patients with BKPyV-DNAemia loads persisting >1000 copies/mL, or exceeding 10 000 copies/mL (or equivalent), or with biopsy-proven BKPyV-nephropathy, immunosuppression should be reduced according to predefined steps targeting antiproliferative drugs, calcineurin inhibitors, or both. In adults without graft dysfunction, kidney allograft biopsy is not required unless the immunological risk is high. For children with persisting BKPyV-DNAemia, allograft biopsy may be considered even without graft dysfunction. Allograft biopsies should be interpreted in the context of all clinical and laboratory findings, including plasma BKPyV-DNAemia. Immunohistochemistry is preferred for diagnosing biopsy-proven BKPyV-nephropathy. Routine screening using the proposed strategies is cost-effective, improves clinical outcomes and quality of life. Kidney retransplantation subsequent to BKPyV-nephropathy is feasible in otherwise eligible recipients if BKPyV-DNAemia is undetectable; routine graft nephrectomy is not recommended. Current studies do not support the usage of leflunomide, cidofovir, quinolones, or IVIGs. Patients considered for experimental treatments (antivirals, vaccines, neutralizing antibodies, and adoptive T cells) should be enrolled in clinical trials.
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Affiliation(s)
- Camille N. Kotton
- Transplant and Immunocompromised Host Infectious Diseases Unit, Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, Toulouse Rangueil University Hospital, INSERM UMR 1291, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), University Paul Sabatier, Toulouse, France
| | - David Wojciechowski
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Michael Eder
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Helmut Hopfer
- Division of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Parmjeet Randhawa
- Division of Transplantation Pathology, The Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
| | - Martina Sester
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany
| | - Patrizia Comoli
- Cell Factory and Pediatric Hematology/Oncology Unit, Department of Mother and Child Health, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Helio Tedesco Silva
- Division of Nephrology, Hospital do Rim, Fundação Oswaldo Ramos, Paulista School of Medicine, Federal University of São Paulo, Brazil
| | - Greg Knoll
- Department of Medicine (Nephrology), University of Ottawa and The Ottawa Hospital, Ottawa, ON, Canada
| | | | - Jennifer Trofe-Clark
- Renal-Electrolyte Hypertension Division, Associated Faculty of the Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA
- Transplantation Division, Associated Faculty of the Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA
| | - Lars Pape
- Pediatrics II, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - David Axelrod
- Kidney, Pancreas, and Living Donor Transplant Programs at University of Iowa, Iowa City, IA
| | - Bryce Kiberd
- Division of Nephrology, Dalhousie University, Halifax, NS, Canada
| | - Germaine Wong
- Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia
- Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, NSW, Australia
- Centre for Transplant and Renal Research, Westmead Hospital, Sydney, NSW, Australia
| | - Hans H. Hirsch
- Division of Transplantation and Clinical Virology, Department of Biomedicine, Faculty of Medicine, University of Basel, Basel, Switzerland
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
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Lannes-Costa PS, Pimentel BADS, Nagao PE. Role of Caveolin-1 in Sepsis – A Mini-Review. Front Immunol 2022; 13:902907. [PMID: 35911737 PMCID: PMC9334647 DOI: 10.3389/fimmu.2022.902907] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 06/23/2022] [Indexed: 11/23/2022] Open
Abstract
Sepsis is a generalized disease characterized by an extreme response to a severe infection. Moreover, challenges remain in the diagnosis, treatment and management of septic patients. In this mini-review we demonstrate developments on cellular pathogenesis and the role of Caveolin-1 (Cav-1) in sepsis. Studies have shown that Cav-1 has a significant role in sepsis through the regulation of membrane traffic and intracellular signaling pathways. In addition, activation of apoptosis/autophagy is considered relevant for the progression and development of sepsis. However, how Cav-1 is involved in sepsis remains unclear, and the precise mechanisms need to be further investigated. Finally, the role of Cav-1 in altering cell permeability during inflammation, in sepsis caused by microorganisms, apoptosis/autophagy activation and new therapies under study are discussed in this mini-review.
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Barrantes FJ. The constellation of cholesterol-dependent processes associated with SARS-CoV-2 infection. Prog Lipid Res 2022; 87:101166. [PMID: 35513161 PMCID: PMC9059347 DOI: 10.1016/j.plipres.2022.101166] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 04/26/2022] [Accepted: 04/27/2022] [Indexed: 01/11/2023]
Abstract
The role of cholesterol in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other coronavirus-host cell interactions is currently being discussed in the context of two main scenarios: i) the presence of the neutral lipid in cholesterol-rich lipid domains involved in different steps of the viral infection and ii) the alteration of metabolic pathways by the virus over the course of infection. Cholesterol-enriched lipid domains have been reported to occur in the lipid envelope membrane of the virus, in the host-cell plasma membrane, as well as in endosomal and other intracellular membrane cellular compartments. These membrane subdomains, whose chemical and physical properties distinguish them from the bulk lipid bilayer, have been purported to participate in diverse phenomena, from virus-host cell fusion to intracellular trafficking and exit of the virions from the infected cell. SARS-CoV-2 recruits many key proteins that participate under physiological conditions in cholesterol and lipid metabolism in general. This review analyses the status of cholesterol and lipidome proteins in SARS-CoV-2 infection and the new horizons they open for therapeutic intervention.
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Affiliation(s)
- Francisco J Barrantes
- Laboratory of Molecular Neurobiology, Institute for Biomedical Research (BIOMED), Faculty of Medical Sciences, UCA-CONICET, Av. Alicia Moreau de Justo 1600, C1107AFF Buenos Aires, Argentina.
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Zhao J, You X, Zeng X. Research progress of BK virus and systemic lupus erythematosus. Lupus 2022; 31:522-531. [PMID: 35264023 DOI: 10.1177/09612033221084259] [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: 11/17/2022]
Abstract
Background: Systemic lupus erythematosus (SLE) is an autoimmune disease in which patients are often infected by viruses due to deficient immunity or immunosuppressant use. BK virus (BKV)mainly affects the kidney and can also cause multiple organ involvement throughout the body, which is similar to SLE. BKV is mostly a latent infection in vivo. The incidence of virus reactivation is higher in SLE patients. Reactivation of BKV can induce the production of autoantibodies, thereby promoting the occurrence and development of SLE.Purpose: Aim of this article is to review the prevalence and pathegenesis of BKV infection in SLE patients.Method: The literature search was conducted using four different databases including PubMed, Cochrane Library, Scopus and Web of Science.Results: BK virus is higher infection and reactivation in SLE patients. The "hapten carrier" mechanism may lead to the production of autoantibodies. Some immunosuppressive drugs, like leflumide and hydroxychloroquine, may show a protective effect.Conclusions: BKV infection plays a role in the occurrence and development of SLE, and its significance deserves further exploration.
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Affiliation(s)
- Jiawei Zhao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 34732Peking Union Medical College, Beijing, China
| | - Xin You
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 34732Peking Union Medical College, Beijing, China
| | - Xiaofeng Zeng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 34732Peking Union Medical College, Beijing, China
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Moriyama T, Hasegawa F, Miyabe Y, Akiyama K, Karasawa K, Uchida K, Nitta K. Intracellular trafficking pathway of albumin in glomerular epithelial cells. Biochem Biophys Res Commun 2021; 574:97-103. [PMID: 34450430 DOI: 10.1016/j.bbrc.2021.08.043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 08/18/2021] [Indexed: 10/20/2022]
Abstract
The intracellular trafficking pathway of albumin in podocytes remains controversial. We therefore analysed albumin endocytosis through caveolae, subsequent transcytosis, and exocytosis. In Western blot and immunofluorescence analysis in vitro, methyl-beta-cyclodextrin (MBCD) treatment significantly decreased the expression of caveolin-1 and albumin in cultured human podocytes after incubation with albumin; additionally, MBCD interfered with albumin endocytosis through caveolae in the experiment using Transwell plates. In the immunofluorescence analysis, albumin was incubated with cultured human podocytes, and colocalisation analysis with organelles and cytoskeletons in the podocytes showed that albumin particles colocalised with caveolin-1 and Fc-receptor but not clathrin in endocytosis, colocalised with actin cytoskeleton but not microtubules in transcytosis, and colocalised with early endosomes and lysosomes but not proteasome, endoplasmic reticulum, or Golgi apparatus. In the electron microscopic analysis of podocytes in nephrotic syndrome model mice, gold-labelled albumin was shown as endocytosis, transcytosis, and exocytosis with caveolae. These results indicate the intracellular trafficking of albumin through podocytes. Albumin enters through caveolae with the Fc-receptor, moves along actin, and reaches the early endosome, where some of them are sorted for lysosomal degradation, and others are directly transported outside the cells through exocytosis. This intracellular pathway may be a new aetiological hypothesis for albuminuria.
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Affiliation(s)
- Takahito Moriyama
- Department of Nephrology, Tokyo Women's Medical University, Tokyo, Japan.
| | - Fumio Hasegawa
- Department of Nephrology, Tokyo Women's Medical University, Tokyo, Japan.
| | - Yoei Miyabe
- Department of Nephrology, Tokyo Women's Medical University, Tokyo, Japan.
| | - Kenichi Akiyama
- Department of Nephrology, Tokyo Women's Medical University, Tokyo, Japan.
| | - Kazunori Karasawa
- Department of Nephrology, Tokyo Women's Medical University, Tokyo, Japan.
| | - Keiko Uchida
- Department of Nephrology, Tokyo Women's Medical University, Tokyo, Japan.
| | - Kosaku Nitta
- Department of Nephrology, Tokyo Women's Medical University, Tokyo, Japan.
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Ren Y, Li L, Wang MM, Cao LP, Sun ZR, Yang ZZ, Zhang W, Zhang P, Nie SN. Pravastatin attenuates sepsis-induced acute lung injury through decreasing pulmonary microvascular permeability via inhibition of Cav-1/eNOS pathway. Int Immunopharmacol 2021; 100:108077. [PMID: 34464887 DOI: 10.1016/j.intimp.2021.108077] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 08/08/2021] [Accepted: 08/12/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Disruption of alveolar endothelial barrier caused by inflammation drives the progression of septic acute lung injury (ALI). Pravastatin, an inhibitor of HMG Co-A reductase, has potent anti-inflammatory effects. In the present study, we aim to explore the beneficial role of pravastatin in sepsis-induced ALI and its related mechanisms. METHODS A septic ALI model was established by cecal ligation and puncture (CLP) in mice. The pulmonary microvascular endothelial cells (PMVECs) were challenged with lipopolysaccharide (LPS). The pathological changes in lung tissues were examined by HE staining. The pulmonary microvascular permeability was determined by lung wet-to-dry (W/D) weight ratio and Evans blue staining. The total protein concentration in bronchoalveolar lavage fluid (BALF) was detected by BCA assay. The levels of TNF-α, IL-1β, and IL-6 were assessed by qRT-PCR and ELISA. Apoptosis was determined by flow cytometry and TUNEL. Western blotting was performed for detection of target protein levels. The expression of VE-Cadherin in lung tissues was evaluated by immunohistochemical staining. RESULTS Pravastatin improved survival rate, attenuated lung pathological changes and reduced pulmonary microvascular permeability in septic mice. In addition, pravastatin restrained sepsis-induced inflammatory response and apoptosis in the lung tissues and PMVECs. Moreover, pravastatin up-regulated the levels of junction proteins ZO-1, JAM-C, and VE-Cadherin. Finally, pravastatin suppressed inflammation, apoptosis and enhanced the expression of junction proteins via regulating Cav-1/eNOS signaling pathway in LPS-exposed PMVECs. CONCLUSION Pravastatin ameliorates sepsis-induced ALI through improving alveolar endothelial barrier disruption via modulating Cav-1/eNOS pathway, which may be an effective candidate for treating septic ALI.
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Affiliation(s)
- Yi Ren
- Department of Emergency Medicine, Jinling Clinical Medical College of Nanjing Medical University, Nanjing 210002, Jiangsu Province, PR China; Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, PR China
| | - Liang Li
- Department of Emergency Medicine, Jinling Clinical Medical College of Nanjing Medical University, Nanjing 210002, Jiangsu Province, PR China; Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, PR China
| | - Meng-Meng Wang
- Department of Emergency Medicine, Jinling Clinical Medical College of Nanjing Medical University, Nanjing 210002, Jiangsu Province, PR China; Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, PR China
| | - Li-Ping Cao
- Department of Emergency Medicine, Jinling Clinical Medical College of Nanjing Medical University, Nanjing 210002, Jiangsu Province, PR China; Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, PR China
| | - Zhao-Rui Sun
- Department of Emergency Medicine, Jinling Clinical Medical College of Nanjing Medical University, Nanjing 210002, Jiangsu Province, PR China; Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, PR China
| | - Zhi-Zhou Yang
- Department of Emergency Medicine, Jinling Clinical Medical College of Nanjing Medical University, Nanjing 210002, Jiangsu Province, PR China; Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, PR China
| | - Wei Zhang
- Department of Emergency Medicine, Jinling Clinical Medical College of Nanjing Medical University, Nanjing 210002, Jiangsu Province, PR China; Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, PR China
| | - Peng Zhang
- Department of Emergency Medicine, Jinling Clinical Medical College of Nanjing Medical University, Nanjing 210002, Jiangsu Province, PR China; Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, PR China
| | - Shi-Nan Nie
- Department of Emergency Medicine, Jinling Clinical Medical College of Nanjing Medical University, Nanjing 210002, Jiangsu Province, PR China; Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, PR China.
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Orlowski S, Mourad JJ, Gallo A, Bruckert E. Coronaviruses, cholesterol and statins: Involvement and application for Covid-19. Biochimie 2021; 189:51-64. [PMID: 34153377 PMCID: PMC8213520 DOI: 10.1016/j.biochi.2021.06.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 06/01/2021] [Accepted: 06/14/2021] [Indexed: 12/17/2022]
Abstract
The infectious power of coronaviruses is dependent on cholesterol present in the membranes of their target cells. Indeed, the virus enters the infected cell either by fusion or by endocytosis, in both cases involving cholesterol-enriched membrane microdomains. These membrane domains can be disorganized in-vitro by various cholesterol-altering agents, including statins that inhibit cell cholesterol biosynthesis. As a consequence, numerous cell physiology processes, such as signaling cascades, can be compromised. Also, some examples of anti-bacterial and anti-viral effects of statins have been observed for infectious agents known to be cholesterol dependent. In-vivo, besides their widely-reported hypocholesterolemic effect, statins display various pleiotropic effects mediated, at least partially, by perturbation of membrane microdomains as a consequence of the alteration of endogenous cholesterol synthesis. It should thus be worth considering a high, but clinically well-tolerated, dose of statin to treat Covid-19 patients, in the early phase of infection, to inhibit virus entry into the target cells, in order to control the viral charge and hence avoid severe clinical complications. Based on its efficacy and favorable biodisposition, an option would be considering Atorvastatin, but randomized controlled clinical trials are required to test this hypothesis. This new therapeutic proposal takes benefit from being a drug repurposing, applied to a widely-used drug presenting a high efficiency-to-toxicity ratio. Additionally, this therapeutic strategy avoids any risk of drug resistance by viral mutation since it is host-targeted. Noteworthy, the same pharmacological approach could also be proposed to address different animal coronavirus endemic infections that are responsible for heavy economic losses.
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Affiliation(s)
- Stéphane Orlowski
- Institute for Integrative Biology of the Cell (I2BC), CNRS UMR 9198, and CEA / DRF / Institut des Sciences du Vivant Frédéric-Joliot / SB2SM, and Université Paris-Saclay, 91191, Gif-sur-Yvette, Cedex, France.
| | - Jean-Jacques Mourad
- Department of Internal Medicine and ESH Excellence Centre, Groupe Hospitalier Paris Saint-Joseph, Paris, France.
| | - Antonio Gallo
- Department of Endocrinology and Prevention of Cardiovascular Diseases, Institute of Cardiometabolism and Nutrition (ICAN), La Pitié-Salpêtrière Hospital, AP-HP, Paris, France.
| | - Eric Bruckert
- Department of Endocrinology and Prevention of Cardiovascular Diseases, Institute of Cardiometabolism and Nutrition (ICAN), La Pitié-Salpêtrière Hospital, AP-HP, Paris, France.
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Proto MC, Fiore D, Piscopo C, Pagano C, Galgani M, Bruzzaniti S, Laezza C, Gazzerro P, Bifulco M. Lipid homeostasis and mevalonate pathway in COVID-19: Basic concepts and potential therapeutic targets. Prog Lipid Res 2021; 82:101099. [PMID: 33915202 PMCID: PMC8074527 DOI: 10.1016/j.plipres.2021.101099] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/21/2022]
Abstract
Despite encouraging progresses achieved in the management of viral diseases, efficient strategies to counteract infections are still required. The current global challenge highlighted the need to develop a rapid and cost-effective strategy to counteract the SARS-CoV-2 pandemic. Lipid metabolism plays a crucial role in viral infections. Viruses can use the host lipid machinery to support their life cycle and to impair the host immune response. The altered expression of mevalonate pathway-related genes, induced by several viruses, assures survival and spread in host tissue. In some infections, statins, HMG-CoA-reductase inhibitors, reduce cholesterol in the plasma membrane of permissive cells resulting in lower viral titers and failure to internalize the virus. Statins can also counteract viral infections through their immunomodulatory, anti-inflammatory and anti-thrombotic effects. Beyond statins, interfering with the mevalonate pathway could have an adjuvant effect in therapies aimed at mitigating endothelial dysfunction and deregulated inflammation in viral infection. In this review we depicted the historical and current evidence highlighting how lipid homeostasis and mevalonate pathway targeting represents a valid approach to rapidly neutralize viruses, focusing our attention to their potential use as effective targets to hinder SARS-CoV-2 morbidity and mortality. Pros and cons of statins and Mevalonate-pathway inhibitors have been also dissected.
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Affiliation(s)
- Maria Chiara Proto
- Department of Pharmacy, University of Salerno, 84084 Fisciano (SA), Italy
| | - Donatella Fiore
- Department of Pharmacy, University of Salerno, 84084 Fisciano (SA), Italy
| | - Chiara Piscopo
- Department of Pharmacy, University of Salerno, 84084 Fisciano (SA), Italy
| | - Cristina Pagano
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", 80131 Naples, Italy
| | - Mario Galgani
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", 80131 Naples, Italy; Institute of Endocrinology and Experimental Oncology, IEOS CNR, 80131 Naples, Italy
| | - Sara Bruzzaniti
- Institute of Endocrinology and Experimental Oncology, IEOS CNR, 80131 Naples, Italy; Department of Biology, University of Naples "Federico II", 80126 Naples, Italy
| | - Chiara Laezza
- Institute of Endocrinology and Experimental Oncology, IEOS CNR, 80131 Naples, Italy
| | - Patrizia Gazzerro
- Department of Pharmacy, University of Salerno, 84084 Fisciano (SA), Italy.
| | - Maurizio Bifulco
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", 80131 Naples, Italy.
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Chan BD, Wong G, Jiang Q, Lee MML, Wong WY, Chen F, Wong WT, Zhu L, Wong FKM, Tai WCS. Longitudinal study of BK Polyomavirus outcomes, risk factors, and kinetics in renal transplantation patients. Microb Pathog 2020; 142:104036. [PMID: 32017958 DOI: 10.1016/j.micpath.2020.104036] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 01/31/2020] [Accepted: 01/31/2020] [Indexed: 11/25/2022]
Abstract
BACKGROUND In the immunocompromised conditions following renal transplantation, BK virus can reactivate and cause BK virus associated nephropathy (BKVN). Increased BK viral loads and extended duration of infection have been linked to development of BKVN. The aim of this study was to observe the incidence of BKV infection and BKVN, and kinetics of infection and disease in renal transplantation recipients. METHODS From 2014 to 2018, we conducted a longitudinal cohort observational study of 139 renal transplantation patients treated at a single clinic. Quantitative PCR assay was conducted to assess longitudinal BK viral loads. Analysis of patient clinical characteristics was performed to determine risk factors for BKV infection and associated disease. RESULTS Of our cohort, 29 (20.9%) patients developed high BK viremia, and 7 (5.0%) developed biopsy-confirmed BKVN. Clinical parameters associated with diabetes (FBS, HbA1c) and hyperlipidemia (TG, TC, LDL-C) were found to be correlated with development of high BK viremia or BKVN. In 3 of 4 patients receiving intravenous immunoglobulin (IVIG) treatment, BK viral loads were reduced by at least 1 log within 2-3 months of administration. Significant differences were measured in BK viral loads and kidney function between BK viremic patients and BKVN patients by 3-9 months post-transplantation. CONCLUSIONS We identified diabetes and hyperlipidemia as potential risk factors for development of high BK viremia and/or BKVN. IVIG was seen to be effective in reducing viral titers. The period 3-9 months post-transplantation was identified as important for development of BKVN from high BK viremia.
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Affiliation(s)
- Brandon Dow Chan
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R, China
| | - Gabriella Wong
- Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
| | - Qing Jiang
- School of Statistics, Beijing Normal University, Beijing, China
| | - Magnolia Muk-Lan Lee
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R, China
| | - Wing-Yan Wong
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R, China
| | - Feifei Chen
- School of Statistics, Renmin University of China, Beijing, China
| | - Wing-Tak Wong
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R, China; State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China
| | - Lixing Zhu
- Department of Mathematics, The Hong Kong Baptist University, Kowloon Tong, Hong Kong S.A.R, China
| | | | - William Chi-Shing Tai
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R, China; State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China.
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Helle F, Brochot E, Handala L, Martin E, Castelain S, Francois C, Duverlie G. Biology of the BKPyV: An Update. Viruses 2017; 9:v9110327. [PMID: 29099746 PMCID: PMC5707534 DOI: 10.3390/v9110327] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 10/30/2017] [Accepted: 10/30/2017] [Indexed: 12/29/2022] Open
Abstract
The BK virus (BKPyV) is a member of the Polyomaviridae family first isolated in 1971. BKPyV causes frequent infections during childhood and establishes persistent infections with minimal clinical implications within renal tubular cells and the urothelium. However, reactivation of BKPyV in immunocompromised individuals may cause serious complications. In particular, with the implementation of more potent immunosuppressive drugs in the last decade, BKPyV has become an emerging pathogen in kidney and bone marrow transplant recipients where it often causes associated nephropathy and haemorrhagic cystitis, respectively. Unfortunately, no specific antiviral against BKPyV has been approved yet and the only therapeutic option is a modulation of the immunosuppressive drug regimen to improve immune control though it may increase the risk of rejection. A better understanding of the BKPyV life cycle is thus needed to develop efficient treatment against this virus. In this review, we provide an update on recent advances in understanding the biology of BKPyV.
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Affiliation(s)
- Francois Helle
- EA4294, Unité de Virologie Clinique et Fondamentale, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, 80054 Amiens, France.
| | - Etienne Brochot
- EA4294, Unité de Virologie Clinique et Fondamentale, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, 80054 Amiens, France.
| | - Lynda Handala
- EA4294, Unité de Virologie Clinique et Fondamentale, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, 80054 Amiens, France.
| | - Elodie Martin
- EA4294, Unité de Virologie Clinique et Fondamentale, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, 80054 Amiens, France.
| | - Sandrine Castelain
- EA4294, Unité de Virologie Clinique et Fondamentale, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, 80054 Amiens, France.
| | - Catherine Francois
- EA4294, Unité de Virologie Clinique et Fondamentale, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, 80054 Amiens, France.
| | - Gilles Duverlie
- EA4294, Unité de Virologie Clinique et Fondamentale, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, 80054 Amiens, France.
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Vigil D, Konstantinov NK, Barry M, Harford AM, Servilla KS, Kim YH, Sun Y, Ganta K, Tzamaloukas AH. BK nephropathy in the native kidneys of patients with organ transplants: Clinical spectrum of BK infection. World J Transplant 2016; 6:472-504. [PMID: 27683628 PMCID: PMC5036119 DOI: 10.5500/wjt.v6.i3.472] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 08/25/2016] [Accepted: 09/08/2016] [Indexed: 02/05/2023] Open
Abstract
Nephropathy secondary to BK virus, a member of the Papoviridae family of viruses, has been recognized for some time as an important cause of allograft dysfunction in renal transplant recipients. In recent times, BK nephropathy (BKN) of the native kidneys has being increasingly recognized as a cause of chronic kidney disease in patients with solid organ transplants, bone marrow transplants and in patients with other clinical entities associated with immunosuppression. In such patients renal dysfunction is often attributed to other factors including nephrotoxicity of medications used to prevent rejection of the transplanted organs. Renal biopsy is required for the diagnosis of BKN. Quantitation of the BK viral load in blood and urine are surrogate diagnostic methods. The treatment of BKN is based on reduction of the immunosuppressive medications. Several compounds have shown antiviral activity, but have not consistently shown to have beneficial effects in BKN. In addition to BKN, BK viral infection can cause severe urinary bladder cystitis, ureteritis and urinary tract obstruction as well as manifestations in other organ systems including the central nervous system, the respiratory system, the gastrointestinal system and the hematopoietic system. BK viral infection has also been implicated in tumorigenesis. The spectrum of clinical manifestations from BK infection and infection from other members of the Papoviridae family is widening. Prevention and treatment of BK infection and infections from other Papovaviruses are subjects of intense research.
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Zhao L, Marciano AT, Rivet CR, Imperiale MJ. Caveolin- and clathrin-independent entry of BKPyV into primary human proximal tubule epithelial cells. Virology 2016; 492:66-72. [PMID: 26901486 DOI: 10.1016/j.virol.2016.02.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 02/05/2016] [Accepted: 02/11/2016] [Indexed: 01/23/2023]
Abstract
BK polyomavirus (BKPyV) is a human pathogen that causes polyomavirus-associated nephropathy and hemorrhagic cystitis in transplant patients. Gangliosides and caveolin proteins have previously been reported to be required for BKPyV infection in animal cell models. Recent studies from our lab and others, however, have indicated that the identity of the cells used for infection studies can greatly influence the behavior of the virus. We therefore wished to re-examine BKPyV entry in a physiologically relevant primary cell culture model, human renal proximal tubule epithelial cells. Using siRNA knockdowns, we interfered with expression of UDP-glucose ceramide glucosyltransferase (UGCG), and the endocytic vesicle coat proteins caveolin 1, caveolin 2, and clathrin heavy chain. The results demonstrate that while BKPyV does require gangliosides for efficient infection, it can enter its natural host cells via a caveolin- and clathrin-independent pathway. The results emphasize the importance of studying viruses in a relevant cell culture model.
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Affiliation(s)
- Linbo Zhao
- Doctoral Program in Cancer Biology, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Anthony T Marciano
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
| | - Courtney R Rivet
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
| | - Michael J Imperiale
- Doctoral Program in Cancer Biology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
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Type I Interferon Counteracts Antiviral Effects of Statins in the Context of Gammaherpesvirus Infection. J Virol 2016; 90:3342-54. [PMID: 26739055 DOI: 10.1128/jvi.02277-15] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 12/30/2015] [Indexed: 12/14/2022] Open
Abstract
UNLABELLED The cholesterol synthesis pathway is a ubiquitous cellular biosynthetic pathway that is attenuated therapeutically by statins. Importantly, type I interferon (IFN), a major antiviral mediator, also depresses the cholesterol synthesis pathway. Here we demonstrate that attenuation of cholesterol synthesis decreases gammaherpesvirus replication in primary macrophages in vitro and reactivation from peritoneal exudate cells in vivo. Specifically, the reduced availability of the intermediates required for protein prenylation was responsible for decreased gammaherpesvirus replication in statin-treated primary macrophages. We also demonstrate that statin treatment of a chronically infected host attenuates gammaherpesvirus latency in a route-of-infection-specific manner. Unexpectedly, we found that the antiviral effects of statins are counteracted by type I IFN. Our studies suggest that type I IFN signaling counteracts the antiviral nature of the subdued cholesterol synthesis pathway and offer a novel insight into the utility of statins as antiviral agents. IMPORTANCE Statins are cholesterol synthesis inhibitors that are therapeutically administered to 12.5% of the U.S. POPULATION Statins attenuate the replication of diverse viruses in culture; however, this attenuation is not always obvious in an intact animal model. Further, it is not clear whether statins alter parameters of highly prevalent chronic herpesvirus infections. We show that statin treatment attenuated gammaherpesvirus replication in primary immune cells and during chronic infection of an intact host. Further, we demonstrate that type I interferon signaling counteracts the antiviral effects of statins. Considering the fact that type I interferon decreases the activity of the cholesterol synthesis pathway, it is intriguing to speculate that gammaherpesviruses have evolved to usurp the type I interferon pathway to compensate for the decreased cholesterol synthesis activity.
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Mbianda C, El-Meanawy A, Sorokin A. Mechanisms of BK virus infection of renal cells and therapeutic implications. J Clin Virol 2015; 71:59-62. [PMID: 26295751 DOI: 10.1016/j.jcv.2015.08.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Accepted: 08/03/2015] [Indexed: 12/18/2022]
Abstract
BK virus (BKV) causes BKV nephritis in renal transplant patients and contributes significantly to the increase of probability of graft loss. BKV, being latent in the urogenital tract, is likely to be transported with the donor kidney to recipients and following reactivation replicates in the nucleus of renal epithelial tubular cells. BKV daughter viruses are released and enter other renal epithelial cells to spread infection. There are still a lot of unknown factors about the mechanism and kinetics of BKV infection. The treatment of BKV infection, with exception of reduction in immunosuppression which increases the risk of allograft rejection, is almost exclusively limited to application of anti-viral drugs with rather inconsistent results. The shortcomings of anti-viral therapies demand the understanding of early steps of infection of permissive cells by BK virus in hope that adequate interventional therapies preventing infection of cells with BK virus could be developed. This review describes the BKV entry in target human cells, intracellular trafficking pathways of BKV particles and potential therapeutic implications based on understanding of mechanisms of BKV infection of renal cells.
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Affiliation(s)
- Christiane Mbianda
- Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Ashraf El-Meanawy
- Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Andrey Sorokin
- Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
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Gabardi S, Ramasamy S, Kim M, Klasek R, Carter D, Mackenzie MR, Chandraker A, Tan CS. Impact of HMG-CoA reductase inhibitors on the incidence of polyomavirus-associated nephropathy in renal transplant recipients with human BK polyomavirus viremia. Transpl Infect Dis 2015; 17:536-43. [PMID: 25989423 PMCID: PMC4529764 DOI: 10.1111/tid.12402] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 03/27/2015] [Accepted: 04/17/2015] [Indexed: 12/16/2022]
Abstract
BACKGROUND Up to 20% of renal transplant recipients (RTR) will develop human BK polyomavirus (BKPyV) viremia. BKPyV viremia is a pre-requisite of polyomavirus-associated nephropathy (PyVAN). Risk of BKPyV infections increases with immunosuppression. Currently, the only effective therapy against PyVAN is reductions in immunosuppression, but this may increase the risk of rejection. In vitro data have shown that pravastatin dramatically decreased caveolin-1 expression in human renal proximal tubular epithelial cells (HRPTEC) and suppressed BKPyV infection in these cells. Based on these data, we postulated that statin therapy may prevent the progression of BKPyV viremia to PyVAN. PATIENTS AND METHODS A multicenter, retrospective study was conducted in adult RTR transplanted between July 2005 and March 2012. All patients with documented BKPyV viremia (viral load >500 copies/mL on 2 consecutive tests) were included. Group I consisted of patients taking a statin before the BKPyV viremia diagnosis (n = 32), and Group II had no statin exposure before or after the BKPyV viremia diagnosis (n = 36). The primary endpoint was the incidence of PyVAN. RESULTS Demographic data, transplant characteristics, and the degree of immunosuppression (i.e., induction/maintenance therapies, rejection treatment) were similar between the groups, with the exception of more diabetics in Group I. The incidence of PyVAN was comparable between the 2 groups (Group I = 28.1% vs. Group II = 41.7%; P = 0.312). CONCLUSIONS Despite the proven in vitro effectiveness of pravastatin preventing BKPyV infection in HRPTEC, statins at doses maximized for cholesterol lowering, in RTR with BKPyV viremia, did not prevent progression to PyVAN.
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Affiliation(s)
- S Gabardi
- Department of Transplant Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Department of Pharmacy Services, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - S Ramasamy
- Department of Pharmacy Services, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - M Kim
- Department of Pharmacy Services, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Department of Cardiology, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - R Klasek
- Department of Pharmacy Services, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - D Carter
- Department of Pharmacy Services, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - M R Mackenzie
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - A Chandraker
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
- Transplantation Research Center, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - C S Tan
- Harvard Medical School, Boston, Massachusetts, USA
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Division of Infectious Disease, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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Moriyama T, Tsuruta Y, Shimizu A, Itabashi M, Takei T, Horita S, Uchida K, Nitta K. The significance of caveolae in the glomeruli in glomerular disease. J Clin Pathol 2011; 64:504-9. [PMID: 21450752 DOI: 10.1136/jcp.2010.087023] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
AIMS The aim of this study was to demonstrate expression of cell membrane invagination 'caveolae' in glomeruli and to correlate this with functional and structural characteristics of the human glomerular diseases. METHODS The expression of caveolin-1 (Cav-1), which is the main component of caveolae, was examined in the glomeruli, and the relationship between Cav-1 expression and pathological and clinical findings was determined in 99 patients with glomerular disease and in 50 renal transplantation donors as controls. RESULTS Cav-1 was expressed very weakly in the controls, and the area of Cav-1 expression relative to the total glomerular area was 0.57±0.65%. However, the area of Cav-1 expression was significantly larger in each glomerular disease (IgA nephropathy, 1.05±1.36%, p<0.05; crescent glomerulonephritis, 1.86±1.19%, p<0.001; minimal change disease, 2.38±1.24%, p<0.001; focal segmental glomerulosclerosis, 2.88±2.05%, p<0.01; membranous nephritis, 4.27±2.95%, p<0.001; membranoproliferative glomerulonephritis, 4.49±3.15%, p<0.001; and diabetic nephropathy, 2.45±1.52%, p<0.001; compared with the controls. Cav-1 expression was significantly decreased in glomerular disease treated with steroids. Co-localisation of Cav-1 and the endothelial marker 'pathologische anatomie leiden-endothelium' was prominent in an immunofluorescence study, and caveolae on the glomerular endothelial cells were observed in electron microscopy. CONCLUSIONS The expression of Cav-1 was significantly increased in the glomeruli of patients with glomerular disease, and it was related to urinary albumin excretion. Cav-1 expression and caveolae were observed in glomerular endothelial cells. It is hypothesised that they play a role in the recovery phase of capillary injury or endocytosis of albumin into endothelial cells. Basic research should be performed to elucidate the role played by Cav-1 and caveolae.
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Affiliation(s)
- Takahito Moriyama
- Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan.
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Unterstab G, Gosert R, Leuenberger D, Lorentz P, Rinaldo CH, Hirsch HH. The polyomavirus BK agnoprotein co-localizes with lipid droplets. Virology 2010; 399:322-31. [DOI: 10.1016/j.virol.2010.01.011] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2009] [Revised: 12/17/2009] [Accepted: 01/07/2010] [Indexed: 11/17/2022]
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[Urologic aspects of Polyomavirus infection]. Prog Urol 2010; 20:11-6. [PMID: 20123522 DOI: 10.1016/j.purol.2009.09.031] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2009] [Revised: 09/17/2009] [Accepted: 09/21/2009] [Indexed: 11/22/2022]
Abstract
JC virus (JCV) and BK virus (BKV) are human Polyomaviruses of the papovavirus family, which also includes a simian vacuolating virus 40 (SV40). Human Polyomaviruses were first isolated in 1971 from the brain (JCV) and urine (BKV) of two different patients. Human Polyomaviruses have a limited and specific tissue tropism infecting the renal tubular cells, the urothelium, the B cells and the brain cells. The virus infects the majority of the human population with seroconversion occurring during adolescence. The detection of the virus may be cytological, pathological, virological or immunological. Following a typically subclinical primary infection, Polyomavirus establishes a life-long persistent infection, especially in the urinary tract. BKV is known to reactivate and cause severe disease in immunosuppressed patients. The presence of Polyomavirus outside conditions of immunosuppression raises the question of its meaning and its therapeutic management. Given the ubiquitous nature of the virus and its strong association with cancer in animal models, they may play an etiological role in human malignancies. Here, we describe the biology of human Polyomaviruses, review their non-malignant and malignant potentials, and discuss the therapeutic aspect.
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Abstract
PURPOSE OF REVIEW Substantial evidence documents the key role of lipid (membrane) rafts and caveolae as microdomains that concentrate a wide variety of receptors and postreceptor components regulated by hormones, neurotransmitters and growth factors. RECENT FINDINGS Recent data document that these microdomains are important in regulating vascular endothelial and smooth muscle cells and renal epithelial cells, and particularly in signal transduction across the plasma membrane. SUMMARY Raft/caveolae domains are cellular regions, including in cardiovascular and renal epithelial cells, which organize a large number of signal transduction components, thereby providing spatially and temporally efficient regulation of cell function.
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Affiliation(s)
- Paul A Insel
- Departments of Pharmacology, University of California, San Diego, California, USA.
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ERRATA. Transplantation 2008. [DOI: 10.1097/tp.0b013e31818b6e81] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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