β1-Integrin blockade prevents podocyte injury in experimental models of minimal change disease
Introduction: Activation of the focal adhesion kinase (FAK) in podocytes is involved in the pathogenesis of minimal change disease (MCD), but the pathway leading to its activation in this disease is unknown. Here, we tested whether podocyte β1 integrin is the upstream modulator of FAK activation and...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | Spanish |
| Published: |
Elsevier
2024-01-01
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| Series: | Nefrología |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0211699522001771 |
| _version_ | 1797356101515083776 |
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| author | Gabriel Cara-Fuentes Rakesh Verma Madhusudan Venkatareddy Colin Bauer Federica Piani Sogut Turkmen Aksoy Neha Vazzalwar Gabriela E. Garcia Mindy Banks Flor A. Ordoñez Carmen de Lucas-Collantes Petter Bjornstad Juan D. González Rodríguez Richard J. Johnson Puneet Garg |
| author_facet | Gabriel Cara-Fuentes Rakesh Verma Madhusudan Venkatareddy Colin Bauer Federica Piani Sogut Turkmen Aksoy Neha Vazzalwar Gabriela E. Garcia Mindy Banks Flor A. Ordoñez Carmen de Lucas-Collantes Petter Bjornstad Juan D. González Rodríguez Richard J. Johnson Puneet Garg |
| author_sort | Gabriel Cara-Fuentes |
| collection | DOAJ |
| description | Introduction: Activation of the focal adhesion kinase (FAK) in podocytes is involved in the pathogenesis of minimal change disease (MCD), but the pathway leading to its activation in this disease is unknown. Here, we tested whether podocyte β1 integrin is the upstream modulator of FAK activation and podocyte injury in experimental models of MCD-like injury. Methods: We used lipopolysaccharide (LPS) and MCD sera to induce MCD-like changes in vivo and in cultured human podocytes, respectively. We performed functional studies using specific β1 integrin inhibitors in vivo and in vitro, and integrated histological analysis, western blotting, and immunofluorescence to assess for morphological and molecular changes in podocytes. By ELISA, we measured serum LPS levels in 35 children with MCD or presumed MCD (idiopathic nephrotic syndrome [INS]) and in 18 healthy controls. Results: LPS-injected mice showed morphological (foot process effacement, and normal appearing glomeruli on light microscopy) and molecular features (synaptopodin loss, nephrin mislocalization, FAK phosphorylation) characteristic of human MCD. Administration of a β1 integrin inhibitor to mice abrogated FAK phosphorylation, and ameliorated proteinuria and podocyte injury following LPS. Children with MCD/INS in relapse had higher serum LPS levels than controls. In cultured human podocytes, β1 integrin blockade prevented cytoskeletal rearrangements following exposure to MCD sera in relapse. Conclusions: Podocyte β1 integrin activation is an upstream mediator of FAK phosphorylation and podocyte injury in models of MCD-like injury. Resumen: Antecedentes: La activación de la quinasa de adhesión focal (FAK) en podocitos juega un papel en la patogénesis de la enfermedad de cambios mínimos (ECM), pero su mecanismo de activación en dicha enfermedad es desconocido. En este estudio investigamos si la integrina β1 de los podocitos modula la activación de FAK y del daño podocitario en modelos experimentales de la ECM. Métodos: Utilizamos lipopolisacárido (LPS) y suero de pacientes con ECM para inducir daño podocitario in vivo e in vitro, respectivamente. Realizamos estudios funcionales usando inhibidores específicos de la integrina β1 in vivo e in vitro, así como estudios histológicos, western blots y técnicas de inmunofluorescencia para evaluar cambios morfológicos y moleculares en podocitos. Usando ELISA medimos los niveles séricos de LPS en 35 niños con ECM o sospecha de ECM (síndrome nefrótico idiopático [SNI]) y en 18 individuos sanos. Resultados: Los ratones inyectados con LPS desarrollaron cambios morfológicos (fusión de pedicelos, con apariencia normal de los glomérulos) y moleculares (pérdida de la expresión de sinaptopodina, cambio en la localización de la nefrina fosforilada y fosforilzación de FAK), que son característicos de la ECM en humanos. La administración de un inhibidor de la integrina β1 en ratones disminuyó la fosforilación de FAK, proteinuria y daño podocitario que ocurre tras la inyección de LPS. En niños con ECM/SNI, los niveles séricos de LPS fueron más elevados que en controles. En cultivos de podocitos humanos, la adicción de un inhibidor de la integrina β1 al suero de niños con ECM en recaída evitó cambios en el citoesqueleto. Conclusiones: La integrina β1 de los podocitos actúa como mediador de la activación de la FAK y del daño podocitario en modelos experimentales de la ECM. |
| first_indexed | 2024-03-08T14:21:49Z |
| format | Article |
| id | doaj.art-0d4c063e87674bbdbe27c4146d42ea59 |
| institution | Directory Open Access Journal |
| issn | 0211-6995 |
| language | Spanish |
| last_indexed | 2024-03-08T14:21:49Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Nefrología |
| spelling | doaj.art-0d4c063e87674bbdbe27c4146d42ea592024-01-14T05:35:08ZspaElsevierNefrología0211-69952024-01-014419099β1-Integrin blockade prevents podocyte injury in experimental models of minimal change diseaseGabriel Cara-Fuentes0Rakesh Verma1Madhusudan Venkatareddy2Colin Bauer3Federica Piani4Sogut Turkmen Aksoy5Neha Vazzalwar6Gabriela E. Garcia7Mindy Banks8Flor A. Ordoñez9Carmen de Lucas-Collantes10Petter Bjornstad11Juan D. González Rodríguez12Richard J. Johnson13Puneet Garg14Corresponding author.; Children's Hospital, CO, United StatesChildren's Hospital, CO, United StatesChildren's Hospital, CO, United StatesChildren's Hospital, CO, United StatesChildren's Hospital, CO, United StatesChildren's Hospital, CO, United StatesChildren's Hospital, CO, United StatesChildren's Hospital, CO, United StatesChildren's Hospital, CO, United StatesChildren's Hospital, CO, United StatesChildren's Hospital, CO, United StatesChildren's Hospital, CO, United StatesChildren's Hospital, CO, United StatesChildren's Hospital, CO, United StatesChildren's Hospital, CO, United StatesIntroduction: Activation of the focal adhesion kinase (FAK) in podocytes is involved in the pathogenesis of minimal change disease (MCD), but the pathway leading to its activation in this disease is unknown. Here, we tested whether podocyte β1 integrin is the upstream modulator of FAK activation and podocyte injury in experimental models of MCD-like injury. Methods: We used lipopolysaccharide (LPS) and MCD sera to induce MCD-like changes in vivo and in cultured human podocytes, respectively. We performed functional studies using specific β1 integrin inhibitors in vivo and in vitro, and integrated histological analysis, western blotting, and immunofluorescence to assess for morphological and molecular changes in podocytes. By ELISA, we measured serum LPS levels in 35 children with MCD or presumed MCD (idiopathic nephrotic syndrome [INS]) and in 18 healthy controls. Results: LPS-injected mice showed morphological (foot process effacement, and normal appearing glomeruli on light microscopy) and molecular features (synaptopodin loss, nephrin mislocalization, FAK phosphorylation) characteristic of human MCD. Administration of a β1 integrin inhibitor to mice abrogated FAK phosphorylation, and ameliorated proteinuria and podocyte injury following LPS. Children with MCD/INS in relapse had higher serum LPS levels than controls. In cultured human podocytes, β1 integrin blockade prevented cytoskeletal rearrangements following exposure to MCD sera in relapse. Conclusions: Podocyte β1 integrin activation is an upstream mediator of FAK phosphorylation and podocyte injury in models of MCD-like injury. Resumen: Antecedentes: La activación de la quinasa de adhesión focal (FAK) en podocitos juega un papel en la patogénesis de la enfermedad de cambios mínimos (ECM), pero su mecanismo de activación en dicha enfermedad es desconocido. En este estudio investigamos si la integrina β1 de los podocitos modula la activación de FAK y del daño podocitario en modelos experimentales de la ECM. Métodos: Utilizamos lipopolisacárido (LPS) y suero de pacientes con ECM para inducir daño podocitario in vivo e in vitro, respectivamente. Realizamos estudios funcionales usando inhibidores específicos de la integrina β1 in vivo e in vitro, así como estudios histológicos, western blots y técnicas de inmunofluorescencia para evaluar cambios morfológicos y moleculares en podocitos. Usando ELISA medimos los niveles séricos de LPS en 35 niños con ECM o sospecha de ECM (síndrome nefrótico idiopático [SNI]) y en 18 individuos sanos. Resultados: Los ratones inyectados con LPS desarrollaron cambios morfológicos (fusión de pedicelos, con apariencia normal de los glomérulos) y moleculares (pérdida de la expresión de sinaptopodina, cambio en la localización de la nefrina fosforilada y fosforilzación de FAK), que son característicos de la ECM en humanos. La administración de un inhibidor de la integrina β1 en ratones disminuyó la fosforilación de FAK, proteinuria y daño podocitario que ocurre tras la inyección de LPS. En niños con ECM/SNI, los niveles séricos de LPS fueron más elevados que en controles. En cultivos de podocitos humanos, la adicción de un inhibidor de la integrina β1 al suero de niños con ECM en recaída evitó cambios en el citoesqueleto. Conclusiones: La integrina β1 de los podocitos actúa como mediador de la activación de la FAK y del daño podocitario en modelos experimentales de la ECM.http://www.sciencedirect.com/science/article/pii/S0211699522001771Enfermedad de cambios mínimosPodocitoIntegrina β1Quinasa de adhesión focal |
| spellingShingle | Gabriel Cara-Fuentes Rakesh Verma Madhusudan Venkatareddy Colin Bauer Federica Piani Sogut Turkmen Aksoy Neha Vazzalwar Gabriela E. Garcia Mindy Banks Flor A. Ordoñez Carmen de Lucas-Collantes Petter Bjornstad Juan D. González Rodríguez Richard J. Johnson Puneet Garg β1-Integrin blockade prevents podocyte injury in experimental models of minimal change disease Nefrología Enfermedad de cambios mínimos Podocito Integrina β1 Quinasa de adhesión focal |
| title | β1-Integrin blockade prevents podocyte injury in experimental models of minimal change disease |
| title_full | β1-Integrin blockade prevents podocyte injury in experimental models of minimal change disease |
| title_fullStr | β1-Integrin blockade prevents podocyte injury in experimental models of minimal change disease |
| title_full_unstemmed | β1-Integrin blockade prevents podocyte injury in experimental models of minimal change disease |
| title_short | β1-Integrin blockade prevents podocyte injury in experimental models of minimal change disease |
| title_sort | β1 integrin blockade prevents podocyte injury in experimental models of minimal change disease |
| topic | Enfermedad de cambios mínimos Podocito Integrina β1 Quinasa de adhesión focal |
| url | http://www.sciencedirect.com/science/article/pii/S0211699522001771 |
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