18 results on '"Kollins, D."'
Search Results
2. POS-546 EFFICACY AND SAFETY OF IPTACOPAN IN IgA NEPHROPATHY: RESULTS OF A RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED PHASE 2 STUDY AT 6 MONTHS
- Author
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Barratt, J., primary, Rovin, B., additional, Zhang, H., additional, Kashihara, N., additional, Maes, B., additional, Rizk, D., additional, Trimarchi, H., additional, Sprangers, B., additional, Meier, M., additional, Kollins, D., additional, Wang, W., additional, Magirr, A., additional, and Perkovic, V., additional
- Published
- 2022
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3. THU0144 Pharmacokinetics and Safety of GP2015, A Proposed Etanercept Biosimilar, Administered Subcutaneously by An Autoinjector or Prefilled Syringe in Healthy Male Subjects
- Author
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Afonso, M., primary, Kollins, D., additional, Macke, L., additional, Woehling, H., additional, and Wuerth, G., additional
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- 2016
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4. FOXP3+ regulatory T-cells in renal allografts: correlation with long-term graft function and acute rejection
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Kollins D, Stoelcker B, Hoffmann U, Tobias Bergler, Reinhold S, Mc, Banas, Rümmele P, Farkas S, Bk, Krämer, and Banas B
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Graft Rejection ,Male ,Time Factors ,Biopsy ,Graft Survival ,Fluorescent Antibody Technique ,Forkhead Transcription Factors ,Middle Aged ,Kidney ,Kidney Transplantation ,T-Lymphocytes, Regulatory ,CD4 Lymphocyte Count ,Treatment Outcome ,Creatinine ,Germany ,Acute Disease ,Humans ,Transplantation, Homologous ,Female ,Transplantation Tolerance ,Prospective Studies ,Biomarkers ,Aged ,Glomerular Filtration Rate - Abstract
The interpretation of a cellular infiltrate as cytotoxic or tolerogen represents an unsolved challenge in current transplantation. The so-called regulatory CD4+ CD25+ T-cells which express the FOXP3 gene have received increasing interest with respect to this question. The existing studies concerning the role of FOXP3+ Tregs for transplant tolerance yielded contradictory results.We examined the numbers of the FOXP3+ Tregs in two groups of renal allograft biopsies both showing cellular infiltration, but either without (n=29) or with signs of acute cellular rejection (n=26), by means of immunofluorescence and correlated the amount of FOXP3+ Tregs to renal function at the time of biopsy and after 1 and 2 years of follow up.The number of FOXP3+ Tregs within infiltrates in non-rejecting biopsies did not correlate with renal function after 1 and 2 years. There were no significant differences in the numbers of FOXP3+ Tregs between biopsies with or without borderline infiltrates. Increased numbers of FOXP3+ Tregs were not associated with an ameliorated severity of graft rejection and did not correlate with outcome after the rejection episode and renal function after 1 and 2 years.The identification of the FOXP3+ regulatory cells within the allograft cannot be considered as an appropriate marker for the interpretation of infiltrates as cytotoxic or tolerogenic or as a prognostic marker for later transplant function.
- Published
- 2011
5. Urine of Patients with Acute Kidney Transplant Rejection Show High Normetanephrine and Decreased 2-Hydroxyestrogens Concentrations
- Author
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Reinhold, S.W., primary, Straub, R.H., additional, Bergler, T., additional, Hoffmann, U., additional, Krüger, B., additional, Banas, M.C., additional, Kammerl, M.C., additional, Kollins, D., additional, Krämer, B.K., additional, and Banas, B., additional
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- 2013
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6. In the Urine, Patients with Acute Kidney Transplant Rejection Show High Normetanephrine and Decreased 2-Hydroxyestrogen Concentrations Two Weeks and Two to Three Months after Transplantation
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Reinhold, S. W., primary, Straub, R. H., additional, Bergler, T., additional, Hoffmann, U., additional, Krüger, B., additional, Banas, M. C., additional, Kammerl, M. C., additional, Kollins, D., additional, Krämer, B. K., additional, and Banas, B., additional
- Published
- 2012
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7. Akute renale Transplantatabstoßung. Aktuelle Aspekte der Diagnostik
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Kollins, D., primary and Banas, B., additional
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- 2011
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8. BAMBI is expressed in endothelial cells and is regulated by lysosomal/autolysosomal degradation
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Xavier, S, Gilbert, V, Rastaldi, M P, Krick, S, Kollins, D, Reddy, A, Bottinger, E, Cohen, C D, and Schlondorff, D
- Subjects
2. Zero hunger
9. Results of a randomized double-blind placebo-controlled Phase 2 study propose iptacopan as an alternative complement pathway inhibitor for IgA nephropathy.
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Zhang H, Rizk DV, Perkovic V, Maes B, Kashihara N, Rovin B, Trimarchi H, Sprangers B, Meier M, Kollins D, Papachristofi O, Milojevic J, Junge G, Nidamarthy PK, Charney A, and Barratt J
- Subjects
- Humans, Treatment Outcome, Complement Pathway, Alternative, Immunologic Factors therapeutic use, Biomarkers, Double-Blind Method, Glomerulonephritis, IGA pathology
- Abstract
Targeting the alternative complement pathway is an attractive therapeutic strategy given its role in the pathogenesis of immunoglobulin A nephropathy (IgAN). Iptacopan (LNP023) is an oral, proximal alternative complement inhibitor that specifically binds to Factor B. Our randomized, double-blind, parallel-group adaptive Phase 2 study (NCT03373461) enrolled patients with biopsy-confirmed IgAN (within previous three years) with estimated glomerular filtration rates of 30 mL/min/1.73 m
2 and over and urine protein 0.75 g/24 hours and over on stable doses of renin angiotensin system inhibitors. Patients were randomized to four iptacopan doses (10, 50, 100, or 200 mg bid) or placebo for either a three-month (Part 1; 46 patients) or a six-month (Part 2; 66 patients) treatment period. The primary analysis evaluated the dose-response relationship of iptacopan versus placebo on 24-hour urine protein-to-creatinine ratio (UPCR) at three months. Other efficacy, safety and biomarker parameters were assessed. Baseline characteristics were generally well-balanced across treatment arms. There was a statistically significant dose-response effect, with 23% reduction in UPCR achieved with iptacopan 200 mg bid (80% confidence interval 8-34%) at three months. UPCR decreased further through six months in iptacopan 100 and 200 mg arms (from a mean of 1.3 g/g at baseline to 0.8 g/g at six months in the 200 mg arm). A sustained reduction in complement biomarker levels including plasma Bb, serum Wieslab, and urinary C5b-9 was observed. Iptacopan was well-tolerated, with no reports of deaths, treatment-related serious adverse events or bacterial infections, and led to strong inhibition of alternative complement pathway activity and persistent proteinuria reduction in patients with IgAN. Thus, our findings support further evaluation of iptacopan in the ongoing Phase 3 trial (APPLAUSE-IgAN; NCT04578834)., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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10. Targeting the Alternative Complement Pathway With Iptacopan to Treat IgA Nephropathy: Design and Rationale of the APPLAUSE-IgAN Study.
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Rizk DV, Rovin BH, Zhang H, Kashihara N, Maes B, Trimarchi H, Perkovic V, Meier M, Kollins D, Papachristofi O, Charney A, and Barratt J
- Abstract
Introduction: Targeting the alternative complement pathway (AP) is an attractive therapeutic strategy because of its role in immunoglobulin A nephropathy (IgAN) pathophysiology. Iptacopan (LNP023), a proximal complement inhibitor that specifically binds to factor B and inhibits the AP, reduced proteinuria and attenuated AP activation in a Phase 2 study of patients with IgAN, thereby supporting the rationale for its evaluation in a Phase 3 study., Methods: APPLAUSE-IgAN (NCT04578834) is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase 3 study enrolling approximately 450 adult patients (aged ≥18 years) with biopsy-confirmed primary IgAN at high risk of progression to kidney failure despite optimal supportive treatment. Eligible patients receiving stable and maximally tolerated doses of angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) will be randomized 1:1 to either iptacopan 200 mg or placebo twice daily for a 24-month treatment period. A prespecified interim analysis (IA) will be performed when approximately 250 patients from the main study population complete the 9-month visit. The primary objective is to demonstrate superiority of iptacopan over placebo in reducing 24-hour urine protein-to-creatinine ratio (UPCR) at the IA and demonstrate the superiority of iptacopan over placebo in slowing the rate of estimated glomerular filtration rate (eGFR) decline (total eGFR slope) estimated over 24 months at study completion. The effect of iptacopan on patient-reported outcomes, safety, and tolerability will be evaluated as secondary outcomes., Conclusions: APPLAUSE-IgAN will evaluate the benefits and safety of iptacopan, a novel targeted therapy for IgAN, in reducing complement-mediated kidney damage and thus slowing or preventing disease progression., (© 2023 Published by Elsevier Inc. on behalf of the International Society of Nephrology.)
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- 2023
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11. Efficacy and safety of Sandoz biosimilar rituximab for active rheumatoid arthritis: 52-week results from the randomized controlled ASSIST-RA trial.
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Smolen JS, Cohen SB, Tony HP, Scheinberg M, Kivitz A, Balanescu A, Gomez-Reino J, Cen L, Poetzl J, Shisha T, and Kollins D
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- Antirheumatic Agents adverse effects, Antirheumatic Agents immunology, Arthritis, Rheumatoid immunology, B-Lymphocytes cytology, Biosimilar Pharmaceuticals adverse effects, Drug Therapy, Combination methods, Humans, Methotrexate therapeutic use, Remission Induction, Rituximab adverse effects, Rituximab immunology, Therapeutic Equivalency, Time Factors, Antirheumatic Agents therapeutic use, Arthritis, Rheumatoid drug therapy, Biosimilar Pharmaceuticals therapeutic use, Rituximab therapeutic use
- Abstract
Objectives: This report provides data for the extent of B cell depletion and recovery, efficacy, safety and immunogenicity of Sandoz rituximab (SDZ-RTX; GP2013; Rixathon®) compared with reference rituximab (Ref-RTX) up to week 52 of the ASSIST-RA study., Methods: Patients were randomized to SDZ-RTX or Ref-RTX in combination with methotrexate according to the RTX label. The primary endpoint was analysed at week 24. Responders (28-joint DAS [DAS28] decrease from baseline >1.2) at week 24 with residual disease activity (DAS28 ≥2.6) were eligible for a second treatment course between week 24 and 52. Endpoints after week 24 included change from baseline in peripheral B cells, DAS28, ACR 20% response rate (ACR20), Clinical and Simplified Disease Activity Indexes (CDAI, SDAI) and HAQ disability index (HAQ-DI). Safety and immunogenicity were assessed by the incidence of adverse events and antidrug antibodies., Results: Primary and secondary endpoints up to week 24 were met. Overall, 260/312 randomized patients completed treatment up to week 52. SDZ-RTX resulted in B cell concentrations over time similar to Ref-RTX. The efficacy of SDZ-RTX was similar to Ref-RTX up to week 52, as measured by DAS28, ACR20/50/70, CDAI, SDAI and HAQ-DI. Safety of SDZ-RTX was similar to Ref-RTX regarding frequency, type and severity of adverse events, which were consistent with the known Ref-RTX safety profile. The incidence of antidrug antibodies was low and transient similarly across treatment groups., Conclusion: SDZ-RTX demonstrated similar B cell concentrations over time, efficacy, safety and immunogenicity to Ref-RTX over 52 weeks of the ASSIST-RA study., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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12. Brief Report: Safety and Immunogenicity of Rituximab Biosimilar GP 2013 After Switch From Reference Rituximab in Patients With Active Rheumatoid Arthritis.
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Tony HP, Krüger K, Cohen SB, Schulze-Koops H, Kivitz AJ, Jeka S, Vereckei E, Cen L, Kring L, and Kollins D
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- Adolescent, Adult, Aged, Anaphylaxis chemically induced, Antirheumatic Agents adverse effects, Arthritis, Rheumatoid epidemiology, Biosimilar Pharmaceuticals adverse effects, Double-Blind Method, Drug Substitution adverse effects, Drug Substitution trends, Female, Humans, Immunogenetic Phenomena drug effects, Immunogenetic Phenomena physiology, Infusions, Intravenous, Male, Middle Aged, Rituximab adverse effects, Young Adult, Antirheumatic Agents administration & dosage, Arthritis, Rheumatoid drug therapy, Biosimilar Pharmaceuticals administration & dosage, Drug Substitution methods, Internationality, Rituximab administration & dosage
- Abstract
Objective: Comparable clinical efficacy of the rituximab (RTX) biosimilar GP2013 and reference RTX has been established in blinded randomized trials. However, when switching from a reference biologic to a biosimilar, potential safety implications are often an important consideration. Therefore, the aim of this study was to evaluate the safety of switching from reference RTX to RTX biosimilar GP2013 compared with treatment continuation with reference RTX in patients with rheumatoid arthritis (RA)., Methods: In this multinational, randomized, double-blind, parallel-group safety study, 107 patients with RA who had previously received treatment (of any duration) with reference RTX as part of routine practice and who required continuation of treatment were randomized to receive either GP2013 or to continue treatment with reference RTX. All patients received a stable dosage of methotrexate and folic acid during the study. Study assessments included the incidence of hypersensitivity, infusion-related and anaphylactic reactions, immunogenicity (antidrug antibodies), and general safety., Results: Regardless of whether patients switched to GP2013 or continued treatment with reference RTX, the incidences of hypersensitivity (9.4% and 11.1%, respectively) and infusion-related reactions (11.3% and 18.5%, respectively) were similarly low. Only 1 patient (in the reference RTX group) developed antidrug antibodies to RTX after starting study treatment. No neutralizing antidrug antibodies were observed. Antidrug antibodies were not associated with adverse events (AEs). No clinically meaningful differences in the rate of AEs were observed between treatment groups., Conclusion: No safety risks were detected when patients switched from reference RTX to GP2013. The safety profiles of patients in both treatment groups were similar, although the study was not powered for statistical testing of equivalence in safety., (© 2018, American College of Rheumatology.)
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- 2019
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13. GP2015, a proposed etanercept biosimilar: Pharmacokinetic similarity to its reference product and comparison of its autoinjector device with prefilled syringes.
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von Richter O, Skerjanec A, Afonso M, Sanguino Heinrich S, Poetzl J, Woehling H, Velinova M, Koch A, Kollins D, Macke L, and Wuerth G
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- Adolescent, Adult, Area Under Curve, Biosimilar Pharmaceuticals adverse effects, Biosimilar Pharmaceuticals pharmacokinetics, Cross-Over Studies, Double-Blind Method, Etanercept adverse effects, Etanercept pharmacokinetics, Follow-Up Studies, Humans, Immunosuppressive Agents adverse effects, Immunosuppressive Agents pharmacokinetics, Injections, Subcutaneous, Male, Middle Aged, Syringes, Therapeutic Equivalency, Young Adult, Biosimilar Pharmaceuticals administration & dosage, Etanercept administration & dosage, Immunosuppressive Agents administration & dosage
- Abstract
Aims: To assess pharmacokinetics (PK) and safety of GP2015, a proposed etanercept biosimilar, in two studies: comparison with etanercept originator (ETN, bioequivalence study) and comparison of GP2015 administered via an autoinjector (AI) or prefilled syringes (PFS, delivery study)., Methods: Both studies were randomized, two-sequence, two-period, crossover studies conducted in healthy male subjects. In the bioequivalence study, subjects were randomized to receive a single 50 mg subcutaneous (s.c.) injection of GP2015 or ETN. In the delivery study, subjects were randomized to receive a single 50 mg s.c. injection of GP2015 via AI or PFS. Following a wash-out period of 35 days, subjects in the bioequivalence study received single 50 mg s.c. injection of GP2015 or ETN, and subjects in the delivery study received single 50 mg s.c. injection of GP2015 via AI or PFS., Results: The geometric mean ratios (90% confidence interval) of GP2015/ETN for C
max (1.11 [1.05-1.17]), AUC0-tlast (0.98 [0.94-1.02]) and AUC0-inf (0.96 [0.93-1.00]) were within the predefined bioequivalence range of 0.80-1.25. The geometric mean ratios (90% confidence interval) of AI/PFS for Cmax (1.01 [0.94-1.08]), AUC0-tlast (1.01 [0.95-1.07]) and AUC0-inf (1.01 [0.96-1.07]) were also within the range 0.80-1.25. No new safety issues were reported. Three subjects had low titres of non-neutralising anti-drug antibodies during a follow-up visit in the bioequivalence study., Conclusions: The PK of GP2015 was similar to ETN, demonstrating bioequivalence. The safety profile of GP2015 was consistent with previous reports for ETN. The GP2015 AI provided equivalent dosing and tolerability to the GP2015 PFS., (© 2016 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2017
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14. Lipoxygenase products in the urine correlate with renal function and body temperature but not with acute transplant rejection.
- Author
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Reinhold SW, Scherl T, Stölcker B, Bergler T, Hoffmann U, Weingart C, Banas MC, Kollins D, Kammerl MC, Krüger B, Kaess B, Krämer BK, and Banas B
- Subjects
- Acute Disease, Adult, Female, Graft Rejection enzymology, Graft Rejection etiology, Graft Rejection pathology, Humans, Kidney Transplantation adverse effects, Lipoxygenase metabolism, Male, Middle Aged, 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid urine, Body Temperature, Graft Rejection urine, Hydroxyeicosatetraenoic Acids urine, Kidney physiology, Leukotriene B4 urine, Leukotriene E4 urine
- Abstract
Acute transplant rejection is the leading cause of graft loss in the first months after kidney transplantation. Lipoxygenase products mediate pro- and anti-inflammatory actions and thus we aimed to correlate the histological reports of renal transplant biopsies with urinary lipoxygenase products concentrations to evaluate their role as a diagnostic marker. This study included a total of 34 kidney transplant recipients: 17 with an acute transplant rejection and 17 controls. LTE4, LTB4, 12-HETE and 15-HETE concentrations were measured by enzyme immunoassay. Urinary lipoxygenase product concentrations were not significantly changed during an acute allograft rejection. Nevertheless, LTB4 concentrations correlated significantly with the body temperature (P ≤ 0.05) 3 months after transplantation, and 12- and 15-HETE concentrations correlated significantly with renal function (P ≤ 0.05) 2 weeks after transplantation. In conclusion, our data show a correlation for LTB4 with the body temperature 3 months after transplantation and urinary 12- and 15-HETE concentrations correlate positively with elevated serum creatinine concentrations but do not predict acute allograft rejection.
- Published
- 2013
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15. Complete recovery after near-fatal multifocal embolization of giant cardiac thrombus: importance of rapid cerebrovascular intervention.
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Kollins D, Birner C, Mueller T, Schuierer G, and Luchner A
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- Anticoagulants therapeutic use, Arterial Occlusive Diseases etiology, Basilar Artery, Heparin therapeutic use, Humans, Male, Middle Aged, Popliteal Artery, Viscera blood supply, Embolectomy methods, Embolism etiology, Heart Diseases drug therapy, Thrombosis drug therapy
- Published
- 2013
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16. Accelerated reendothelialization, increased neovascularization and erythrocyte extravasation after arterial injury in BAMBI-/- mice.
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Guillot N, Kollins D, Badimon JJ, Schlondorff D, and Hutter R
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- Animals, Cell Movement, Cell Proliferation, Endothelial Cells metabolism, Endothelial Cells pathology, Femoral Artery metabolism, Hemorrhage pathology, Male, Membrane Proteins genetics, Mice, Muscle, Smooth, Vascular metabolism, Muscle, Smooth, Vascular pathology, Myocytes, Smooth Muscle metabolism, Myocytes, Smooth Muscle pathology, Neovascularization, Pathologic, Signal Transduction, Tunica Intima metabolism, Vascular System Injuries genetics, Vascular System Injuries pathology, Erythrocytes pathology, Femoral Artery injuries, Membrane Proteins deficiency, Tunica Intima injuries, Vascular System Injuries metabolism, Wound Healing
- Abstract
Background: Intimal injury rapidly activates TGFβ and enhances vascular repair by the growth of endothelial (EC) and vascular smooth muscle cells (VSMC). The response to the TGFβ family of growth factors can be modified by BAMBI (BMP, Activin, Membrane Bound Inhibitor) acting as a non-signaling, competitive antagonist of TGFβ type I receptors such as ALK 1 and 5. In vivo the effect of BAMBI will depend on its cell-specific expression and of that of the ALK type receptors. We recently reported EC restricted BAMBI expression and genetic elimination of BAMBI resulting in an in vitro and in vivo phenotype characterized by endothelial activation and proliferation involving alternative pathway activation by TGFβ through ALK 1., Methodology/principal Findings: To test the hypothesis that BAMBI modulates arterial response to injury via its effects on endothelial repair and arterial wall neovascularization we used a model of femoral arterial denudation injury in wild type (WT) and BAMBI(-/-) mice. Arterial response was evaluated at 2 and 4 weeks after luminal endothelial denudation of femoral arteries. The BAMBI(-/-) genotype mice showed accelerated luminal endothelial repair at 2 weeks and a highly unusual increase in arterial wall neovascularization compared to WT mice. The exuberant intimal and medial neovessel formation with BAMBI(-/-) genotype was also associated with significant red blood cell extravasation. The bleeding into the neointima at 2 weeks transiently increased it's area in the BAMBI(-/-)genotype despite the faster luminal endothelial repair in this group. Vascular smooth muscle cells were decreased at 2 weeks in BAMBI(-/-) mice, but comparable to wild type at 4 weeks., Conclusions/significance: The absence of BAMBI results in a highly unusual surge in arterial wall neovascularization that surprisingly mimiks features of intra-plaque hemorrhage of advanced atheroma in a mechanical injury model. This suggests important effects of BAMBI on arterial EC homeostasis that need to be further studied in a model of inflammatory atherosclerosis.
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- 2013
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17. BAMBI regulates angiogenesis and endothelial homeostasis through modulation of alternative TGFβ signaling.
- Author
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Guillot N, Kollins D, Gilbert V, Xavier S, Chen J, Gentle M, Reddy A, Bottinger E, Jiang R, Rastaldi MP, Corbelli A, and Schlondorff D
- Subjects
- Animals, Cell Movement physiology, Endothelium, Vascular metabolism, Human Umbilical Vein Endothelial Cells, Humans, Kidney Glomerulus metabolism, Membrane Proteins genetics, Mice, Mice, Knockout, Nephrectomy, Phosphorylation, Endothelial Cells metabolism, Homeostasis physiology, Membrane Proteins metabolism, Neovascularization, Physiologic physiology, Signal Transduction physiology, Transforming Growth Factor beta metabolism
- Abstract
Background: BAMBI is a type I TGFβ receptor antagonist, whose in vivo function remains unclear, as BAMBI(-/-) mice lack an obvious phenotype., Methodology/principal Findings: Identifying BAMBI's functions requires identification of cell-specific expression of BAMBI. By immunohistology we found BAMBI expression restricted to endothelial cells and by electron microscopy BAMBI(-/-) mice showed prominent and swollen endothelial cells in myocardial and glomerular capillaries. In endothelial cells over-expression of BAMBI reduced, whereas knock-down enhanced capillary growth and migration in response to TGFβ. In vivo angiogenesis was enhanced in matrigel implants and in glomerular hypertrophy after unilateral nephrectomy in BAMBI(-/-) compared to BAMBI(+/+) mice consistent with an endothelial phenotype for BAMBI(-/-) mice. BAMBI's mechanism of action in endothelial cells was examined by canonical and alternative TGFβ signaling in HUVEC with over-expression or knock-down of BAMBI. BAMBI knockdown enhanced basal and TGFβ stimulated SMAD1/5 and ERK1/2 phosphorylation, while over-expression prevented both., Conclusions/significance: Thus we provide a first description of a vascular phenotype for BAMBI(-/-) mice, and provide in vitro and in vivo evidence that BAMBI contributes to endothelial and vascular homeostasis. Further, we demonstrate that in endothelial cells BAMBI interferes with alternative TGFβ signaling, most likely through the ALK 1 receptor, which may explain the phenotype observed in BAMBI(-/-) mice. This newly described role for BAMBI in regulating endothelial function has potential implications for understanding and treating vascular disease and tumor neo-angiogenesis.
- Published
- 2012
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18. BAMBI is expressed in endothelial cells and is regulated by lysosomal/autolysosomal degradation.
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Xavier S, Gilbert V, Rastaldi MP, Krick S, Kollins D, Reddy A, Bottinger E, Cohen CD, and Schlondorff D
- Subjects
- 3' Untranslated Regions, Animals, Cell Line, Endothelial Cells cytology, Female, Humans, Kidney cytology, Kidney metabolism, Lysosomes genetics, Male, Membrane Proteins genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Autophagy, Endothelial Cells metabolism, Gene Expression Regulation, Lysosomes metabolism, Membrane Proteins metabolism
- Abstract
Background: BAMBI (BMP and Activin Membrane Bound Inhibitor) is considered to influence TGFβ and Wnt signaling, and thereby fibrosis. Surprisingly data on cell type-specific expression of BAMBI are not available. We therefore examined the localization, gene regulation, and protein turnover of BAMBI in kidneys., Methodology/principal Findings: By immunofluorescence microscopy and by mRNA expression, BAMBI is restricted to endothelial cells of the glomerular and some peritubular capillaries and of arteries and veins in both murine and human kidneys. TGFβ upregulated mRNA of BAMBI in murine glomerular endothelial cells (mGEC). LPS did not downregulate mRNA for BAMBI in mGEC or in HUVECs. BAMBI mRNA had a half-life of only 60 minutes and was stabilized by cycloheximide, indicating post-transcriptional regulation due to AU-rich elements, which we identified in the 3' untranslated sequence of both the human and murine BAMBI gene. BAMBI protein turnover was studied in HUVECs with BAMBI overexpression using a lentiviral system. Serum starvation as an inducer of autophagy caused marked BAMBI degradation, which could be totally prevented by inhibition of lysosomal and autolysosomal degradation with bafilomycin, and partially by inhibition of autophagy with 3-methyladenine, but not by proteasomal inhibitors. Rapamycin activates autophagy by inhibiting TOR, and resulted in BAMBI protein degradation. Both serum starvation and rapamycin increased the conversion of the autophagy marker LC3 from LC3-I to LC3-II and also enhanced co-staining for BAMBI and LC3 in autolysosomal vesicles., Conclusions/significance: 1. BAMBI localizes to endothelial cells in the kidney and to HUVECs. 2. BAMBI mRNA is regulated by post-transcriptional mechanisms. 3. BAMBI protein is regulated by lysosomal and autolysosomal degradation. The endothelial localization and the quick turnover of BAMBI may indicate novel, yet to be defined functions of this modulator for TGFβ and Wnt protein actions in the renal vascular endothelium in health and disease.
- Published
- 2010
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