EP300/CBP is crucial for cAMP-PKA pathway to alleviate podocyte dedifferentiation via targeting Notch3 signaling.
Exp Cell Res
; 407(2): 112825, 2021 10 15.
Article
en En
| MEDLINE
| ID: mdl-34506759
ABSTRACT
Podocyte injury is the hallmark of proteinuric glomerular diseases. Notch3 is neo-activated simultaneously in damaged podocytes and podocyte's progenitor cells of FSGS, indicating a unique role of Notch3. We previously showed that activation of cAMP-PKA pathway alleviated podocyte injury possibly via inhibiting Notch3 expression. However, the mechanisms are unknown. In the present study, Notch3 signaling was significantly activated in ADR-induced podocytes in vitro and in PAN nephrosis rats and patients with idiopathic FSGS in vivo, concomitantly with podocyte dedifferentiation. In cultured podocytes, pCPT-cAMP, a selective cAMP-PKA activator, dramatically blocked ADR-induced activation of Notch3 signaling as well as inhibition of cAMP-PKA pathway, thus alleviating the decreased cell viability and podocyte dedifferentiation. Bioinformatics analysis revealed EP300/CBP, a transcriptional co-activator, as a central hub for the crosstalk between these two signaling pathways. Additionally, CREB/KLF15 in cAMP-PKA pathway competed with RBP-J the major transcriptional factor of Notch3 signaling for binding to EP300/CBP. EP300/CBP siRNA significantly inhibited these two signaling transduction pathways and disrupted the interactions between the above major transcriptional factors. These data indicate a crucial role of EP300/CBP in regulating the crosstalk between cAMP-PKA pathway and Notch3 signaling and modulating the phenotypic change of podocytes, and enrich the reno-protective mechanisms of cAMP-PKA pathway.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Fragmentos de Péptidos
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Sialoglicoproteínas
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Glomeruloesclerosis Focal y Segmentaria
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Proteínas Quinasas Dependientes de AMP Cíclico
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AMP Cíclico
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Podocitos
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Proteína p300 Asociada a E1A
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Desdiferenciación Celular
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Receptor Notch3
Tipo de estudio:
Prognostic_studies
Límite:
Adult
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Animals
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Female
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Humans
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Male
Idioma:
En
Año:
2021
Tipo del documento:
Article