Cyclosporin A Impairs the Secretion and Activity of ADAMTS13 (A Disintegrin and Metalloprotease with Thrombospondin Type 1 Repeat)

Hershko, Klilah; Simhadri, Vijaya L.; Blaisdell, Adam; Hunt, Ryan; Newell, Jordan M.; Tseng, Shi‐Chang; Hershko, Alon Y.; Choi, Jae Won; Sauna, Zuben E.; Wu, Andrew; Bram, Richard J.; Komar, Anton A.; Kimchi-Sarfaty, Chava

doi:10.1074/jbc.m112.383968

Cited by 11 publications

(5 citation statements)

References 67 publications

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“…9 Cyclosporine can also reduce levels of ADAMTS13 by inhibiting its secretion or by releasing vWF multimers that can form complexes with ADAMTS13. 16 Infections with several microorganisms such as Aspergillus, cytomegalovirus (CMV), and adenovirus have also been implicated in TA-TMA. 7,[17][18][19][20] Although no direct mechanism has been proposed, infections are a major activator of the alternate complement pathway, which may cause TA-TMA.…”

Section: Risk Factors and Pathogenesismentioning

confidence: 99%

Hematopoietic Stem Cell Transplant-Associated Thrombotic Microangiopathy

Elsallabi

Bhatt

Dhakal

et al. 2015

Clin Appl Thromb Hemost

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Hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal, multifactorial disorder, which may present with thrombocytopenia, hemolysis, acute renal failure, mental status changes and involvement of other organs. The pathogenesis of TA-TMA is complex and includes multiple risk factors such as certain conditioning regimens, calcineurin inhibitors (CNIs), graft-versus-host disease (GVHD), human leukocyte antigen mismatch, and opportunistic infections. The end result of these insults is endothelial injury in the kidney and other organs. Recent studies also indicate a role of complement activation in tissue damage. The lack of sensitive and specific diagnostic tests for TA-TMA often results in delayed diagnosis. Biopsy is not always possible for diagnosis because of the risk of complications such as bleeding. Recently, an emerging role of renal-centered screening approach has been demonstrated, which utilize the monitoring of blood pressure, urine protein, serum lactate dehydrogenase and hemogram for early detection. Therapeutic options are limited, and plasma exchange plays a minor role. Withdrawal of offending agent such as CNIs and the use of rituximab can be effective in some patients. However, the current treatment strategy is suboptimal and associated with high mortality rate. Recently, eculizumab has been utilized in a few patients with good outcomes. Patients, who develop TA-TMA, are also at an increased risk of GVHD, infection, renal, cardiovascular, and other complications, which can contribute to high mortality. Better understanding of molecular pathogenesis, improvement in posttransplant management, leading to early diagnosis, and management of TA-TMA are required to improve outcomes of this fatal entity.

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Section: Risk Factors and Pathogenesismentioning

confidence: 99%

Hematopoietic Stem Cell Transplant-Associated Thrombotic Microangiopathy

Elsallabi

Bhatt

Dhakal

et al. 2015

Clin Appl Thromb Hemost

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“…26 reduction of hCypB levels by siRNA-mediated knockdown or cyclosporin A treatment decreased the secretion of active ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeat); 35 and siRNA-mediated knockdown of hCypB also significantly increased ER stress-induced apoptosis upon tunicamycin treatment. 24 Considering that hCypB is the most abundant cyclophilin in the ER and has highly conserved sequences among organisms, it is likely to play a crucial role in the management of protein folding in the ER.…”

Section: Discussionmentioning

confidence: 99%

An Endoplasmic Reticulum Cyclophilin Cpr5p Rescues Z-type α₁-Antitrypsin from Retarded Folding

Jung¹,

Lim²,

Lee³

et al. 2014

Bulletin of the Korean Chemical Society

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Human α 1 -antitrypsin (α 1 -AT) is a natural inhibitor of neutrophil elastases and has several dozens of genetic variants. Most of the deficient genetic variants of human α 1 -AT are unstable and cause pulmonary emphysema. However, the most clinically significant variant, Z-type α 1 -AT, exhibits retarded protein folding that leads to accumulation of folding intermediates. These aggregate within the endoplasmic reticulum (ER) of hepatocytes, subsequently causing liver cirrhosis as well as emphysema. Here, we studied the role of an ER folding assistant protein Cpr5p on Z-type α 1 -AT folding. Cpr5p was induced > 2-fold in Z-type α 1 -AT-expressing yeast cells compared with the wild type. Knockout of CPR5 exacerbated cytotoxicity of Z-type α 1 -AT, and re-introduction of CPR5 rescued the knockout cells from aggravated cytotoxicity caused by the α 1 -AT variant. Furthermore, Cpr5p co-immunoprecipitated with Z-type α 1 -AT and facilitated its protein folding. Our results suggest that protein-folding diseases may be suppressed by folding assistant proteins at the site of causal protein biosynthesis.

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“…High-dose chemotherapy, calcineurin inhibitors, infection with different viruses, and graft-versus-host disease can lead to direct endothelial damage and classic or alternative complement pathway activation[ 85 , 86 ]. Cyclosporine can reduce levels of ADAMTS13 by inhibiting its secretion or by releasing von Willebrand factor multimers that form complexes with ADAMTS13 [ 87 ]. Immune dysregulation after HSCT can be a reason for anti-CFH antibody formation [ 88 ].…”

Section: Management Of Ahusmentioning

confidence: 99%

“…An indirect comparison of patient-level data from pivotal trials of ravulizumab and eculizumab indicates that there are no significant between-group differences in platelet count and kidney outcomes at 26 weeks, after adjustments for baseline characteristics [ 96 ]. A reduction in dosing frequency is an important element in improving the quality of life in patients with aHUS [ 87 ]. The frequency of infusions has been shown to be one of the most important factors contributing to the improved quality of life for patients switching to ravulizumab [ 97 ].…”

Section: Management Of Ahusmentioning

confidence: 99%

Pharmacological Management of Atypical Hemolytic Uremic Syndrome in Pediatric Patients: Current and Future

Gurevich

Landau

2023

Pediatr Drugs

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Atypical hemolytic uremic syndrome is a thrombotic microangiopathy characterized by hemolysis, thrombocytopenia, and acute kidney injury, usually caused by alternative complement system overactivation due to pathogenic genetic variants or antibodies to components or regulatory factors in this pathway. Previously, a lack of effective treatment for this condition was associated with mortality, end-stage kidney disease, and the risk of disease recurrence after kidney transplantation. Plasma therapy has been used for atypical hemolytic uremic syndrome treatment with inconsistent results. Complement-blocking treatment changed the outcome and prognosis of patients with atypical hemolytic uremic syndrome. Early administration of eculizumab, a monoclonal C5 antibody, leads to improvements in hematologic, kidney, and systemic manifestations in patients with atypical hemolytic uremic syndrome, even with apparent dialysis dependency. Pre- and post-transplant use of eculizumab is effective in the prevention of atypical hemolytic uremic syndrome recurrence. Evidence on eculizumab use in secondary hemolytic uremic syndrome cases is controversial. Recent data favor the restrictive use of eculizumab in carefully selected atypical hemolytic uremic syndrome cases, but close monitoring for relapse after drug discontinuation is emphasized. Prophylaxis for meningococcal infection is important. The long-acting C5 monoclonal antibody ravulizumab is now approved for atypical hemolytic uremic syndrome treatment, enabling a reduction in the dosing frequency and improving the quality of life in patients with atypical hemolytic uremic syndrome. New strategies for additional and novel complement blockage medications in atypical hemolytic uremic syndrome are under investigation.

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Cyclosporin A Impairs the Secretion and Activity of ADAMTS13 (A Disintegrin and Metalloprotease with Thrombospondin Type 1 Repeat)

Cited by 11 publications

References 67 publications

Hematopoietic Stem Cell Transplant-Associated Thrombotic Microangiopathy

Hematopoietic Stem Cell Transplant-Associated Thrombotic Microangiopathy

An Endoplasmic Reticulum Cyclophilin Cpr5p Rescues Z-type α₁-Antitrypsin from Retarded Folding

Pharmacological Management of Atypical Hemolytic Uremic Syndrome in Pediatric Patients: Current and Future

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Cyclosporin A Impairs the Secretion and Activity of ADAMTS13 (A Disintegrin and Metalloprotease with Thrombospondin Type 1 Repeat)

Cited by 11 publications

References 67 publications

Hematopoietic Stem Cell Transplant-Associated Thrombotic Microangiopathy

Hematopoietic Stem Cell Transplant-Associated Thrombotic Microangiopathy

An Endoplasmic Reticulum Cyclophilin Cpr5p Rescues Z-type α1-Antitrypsin from Retarded Folding

Pharmacological Management of Atypical Hemolytic Uremic Syndrome in Pediatric Patients: Current and Future

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An Endoplasmic Reticulum Cyclophilin Cpr5p Rescues Z-type α₁-Antitrypsin from Retarded Folding