Your browser doesn't support javascript.
loading
Polyploid tubular cells initiate a TGF-ß1 controlled loop that sustains polyploidization and fibrosis after acute kidney injury.
De Chiara, Letizia; Semeraro, Roberto; Mazzinghi, Benedetta; Landini, Samuela; Molli, Alice; Antonelli, Giulia; Angelotti, Maria Lucia; Melica, Maria Elena; Maggi, Laura; Conte, Carolina; Peired, Anna Julie; Cirillo, Luigi; Raglianti, Valentina; Magi, Alberto; Annunziato, Francesco; Romagnani, Paola; Lazzeri, Elena.
Afiliación
  • De Chiara L; Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
  • Semeraro R; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
  • Mazzinghi B; Nephrology and Dialysis Unit, Meyer Children's University Hospital, IRCCS, Florence, Italy.
  • Landini S; Medical Genetics Unit, Meyer Children's University Hospital, IRCCS, Florence, Italy.
  • Molli A; Nephrology and Dialysis Unit, Meyer Children's University Hospital, IRCCS, Florence, Italy.
  • Antonelli G; Nephrology and Dialysis Unit, Meyer Children's University Hospital, IRCCS, Florence, Italy.
  • Angelotti ML; Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
  • Melica ME; Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
  • Maggi L; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
  • Conte C; Nephrology and Dialysis Unit, Meyer Children's University Hospital, IRCCS, Florence, Italy.
  • Peired AJ; Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
  • Cirillo L; Nephrology and Dialysis Unit, Meyer Children's University Hospital, IRCCS, Florence, Italy.
  • Raglianti V; Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
  • Magi A; Nephrology and Dialysis Unit, Meyer Children's University Hospital, IRCCS, Florence, Italy.
  • Annunziato F; Department of Information Engineering, University of Florence, Florence, Italy.
  • Romagnani P; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
  • Lazzeri E; Flow Cytometry Diagnostic Center and Immunotherapy (CDCI), Careggi University Hospital, Florence, Italy.
Am J Physiol Cell Physiol ; 325(4): C849-C861, 2023 10 01.
Article en En | MEDLINE | ID: mdl-37642236
Polyploidization of tubular cells (TC) is triggered by acute kidney injury (AKI) to allow survival in the early phase after AKI, but in the long run promotes fibrosis and AKI-chronic kidney disease (CKD) transition. The molecular mechanism governing the link between polyploid TC and kidney fibrosis remains to be clarified. In this study, we demonstrate that immediately after AKI, expression of cell cycle markers mostly identifies a population of DNA-damaged polyploid TC. Using transgenic mouse models and single-cell RNA sequencing we show that, unlike diploid TC, polyploid TC accumulate DNA damage and survive, eventually resting in the G1 phase of the cell cycle. In vivo and in vitro single-cell RNA sequencing along with sorting of polyploid TC shows that these cells acquire a profibrotic phenotype culminating in transforming growth factor (TGF)-ß1 expression and that TGF-ß1 directly promotes polyploidization. This demonstrates that TC polyploidization is a self-sustained mechanism. Interactome analysis by single-cell RNA sequencing revealed that TGF-ß1 signaling fosters a reciprocal activation loop among polyploid TC, macrophages, and fibroblasts to sustain kidney fibrosis and promote CKD progression. Collectively, this study contributes to the ongoing revision of the paradigm of kidney tubule response to AKI, supporting the existence of a tubulointerstitial cross talk mediated by TGF-ß1 signaling produced by polyploid TC following DNA damage.NEW & NOTEWORTHY Polyploidization in tubular epithelial cells has been neglected until recently. Here, we showed that polyploidization is a self-sustained mechanism that plays an important role during chronic kidney disease development, proving the existence of a cross talk between infiltrating cells and polyploid tubular cells. This study contributes to the ongoing revision of kidney adaptation to injury, posing polyploid tubular cells at the center of the process.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor de Crecimiento Transformador beta1 / Lesión Renal Aguda Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Am J Physiol Cell Physiol Asunto de la revista: FISIOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor de Crecimiento Transformador beta1 / Lesión Renal Aguda Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Am J Physiol Cell Physiol Asunto de la revista: FISIOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Estados Unidos