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LPS-Binding Protein Modulates Acute Renal Fibrosis by Inducing Pericyte-to-Myofibroblast Trans-Differentiation through TLR-4 Signaling

During sepsis, the increased synthesis of circulating lipopolysaccharide (LPS)-binding protein (LBP) activates LPS/TLR4 signaling in renal resident cells, leading to acute kidney injury (AKI). Pericytes are the major source of myofibroblasts during chronic kidney disease (CKD), but their involvement...

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Autores principales: Castellano, Giuseppe, Stasi, Alessandra, Franzin, Rossana, Sallustio, Fabio, Divella, Chiara, Spinelli, Alessandra, Netti, Giuseppe Stefano, Fiaccadori, Enrico, Cantaluppi, Vincenzo, Crovace, Antonio, Staffieri, Francesco, Lacitignola, Luca, Grandaliano, Giuseppe, Simone, Simona, Pertosa, Giovanni Battista, Gesualdo, Loreto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696277/
https://www.ncbi.nlm.nih.gov/pubmed/31357597
http://dx.doi.org/10.3390/ijms20153682
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author Castellano, Giuseppe
Stasi, Alessandra
Franzin, Rossana
Sallustio, Fabio
Divella, Chiara
Spinelli, Alessandra
Netti, Giuseppe Stefano
Fiaccadori, Enrico
Cantaluppi, Vincenzo
Crovace, Antonio
Staffieri, Francesco
Lacitignola, Luca
Grandaliano, Giuseppe
Simone, Simona
Pertosa, Giovanni Battista
Gesualdo, Loreto
author_facet Castellano, Giuseppe
Stasi, Alessandra
Franzin, Rossana
Sallustio, Fabio
Divella, Chiara
Spinelli, Alessandra
Netti, Giuseppe Stefano
Fiaccadori, Enrico
Cantaluppi, Vincenzo
Crovace, Antonio
Staffieri, Francesco
Lacitignola, Luca
Grandaliano, Giuseppe
Simone, Simona
Pertosa, Giovanni Battista
Gesualdo, Loreto
author_sort Castellano, Giuseppe
collection PubMed
description During sepsis, the increased synthesis of circulating lipopolysaccharide (LPS)-binding protein (LBP) activates LPS/TLR4 signaling in renal resident cells, leading to acute kidney injury (AKI). Pericytes are the major source of myofibroblasts during chronic kidney disease (CKD), but their involvement in AKI is poorly understood. Here, we investigate the occurrence of pericyte-to-myofibroblast trans-differentiation (PMT) in sepsis-induced AKI. In a swine model of sepsis-induced AKI, PMT was detected within 9 h from LPS injection, as evaluated by the reduction of physiologic PDGFRβ expression and the dysfunctional α-SMA increase in peritubular pericytes. The therapeutic intervention by citrate-based coupled plasma filtration adsorption (CPFA) significantly reduced LBP, TGF-β, and endothelin-1 (ET-1) serum levels, and furthermore preserved PDGFRβ and decreased α-SMA expression in renal biopsies. In vitro, both LPS and septic sera led to PMT with a significant increase in Collagen I synthesis and α-SMA reorganization in contractile fibers by both SMAD2/3-dependent and -independent TGF-β signaling. Interestingly, the removal of LBP from septic plasma inhibited PMT. Finally, LPS-stimulated pericytes secreted LBP and TGF-β and underwent PMT also upon TGF-β receptor-blocking, indicating the crucial pro-fibrotic role of TLR4 signaling. Our data demonstrate that the selective removal of LBP may represent a therapeutic option to prevent PMT and the development of acute renal fibrosis in sepsis-induced AKI.
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spelling pubmed-66962772019-09-05 LPS-Binding Protein Modulates Acute Renal Fibrosis by Inducing Pericyte-to-Myofibroblast Trans-Differentiation through TLR-4 Signaling Castellano, Giuseppe Stasi, Alessandra Franzin, Rossana Sallustio, Fabio Divella, Chiara Spinelli, Alessandra Netti, Giuseppe Stefano Fiaccadori, Enrico Cantaluppi, Vincenzo Crovace, Antonio Staffieri, Francesco Lacitignola, Luca Grandaliano, Giuseppe Simone, Simona Pertosa, Giovanni Battista Gesualdo, Loreto Int J Mol Sci Article During sepsis, the increased synthesis of circulating lipopolysaccharide (LPS)-binding protein (LBP) activates LPS/TLR4 signaling in renal resident cells, leading to acute kidney injury (AKI). Pericytes are the major source of myofibroblasts during chronic kidney disease (CKD), but their involvement in AKI is poorly understood. Here, we investigate the occurrence of pericyte-to-myofibroblast trans-differentiation (PMT) in sepsis-induced AKI. In a swine model of sepsis-induced AKI, PMT was detected within 9 h from LPS injection, as evaluated by the reduction of physiologic PDGFRβ expression and the dysfunctional α-SMA increase in peritubular pericytes. The therapeutic intervention by citrate-based coupled plasma filtration adsorption (CPFA) significantly reduced LBP, TGF-β, and endothelin-1 (ET-1) serum levels, and furthermore preserved PDGFRβ and decreased α-SMA expression in renal biopsies. In vitro, both LPS and septic sera led to PMT with a significant increase in Collagen I synthesis and α-SMA reorganization in contractile fibers by both SMAD2/3-dependent and -independent TGF-β signaling. Interestingly, the removal of LBP from septic plasma inhibited PMT. Finally, LPS-stimulated pericytes secreted LBP and TGF-β and underwent PMT also upon TGF-β receptor-blocking, indicating the crucial pro-fibrotic role of TLR4 signaling. Our data demonstrate that the selective removal of LBP may represent a therapeutic option to prevent PMT and the development of acute renal fibrosis in sepsis-induced AKI. MDPI 2019-07-27 /pmc/articles/PMC6696277/ /pubmed/31357597 http://dx.doi.org/10.3390/ijms20153682 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Castellano, Giuseppe
Stasi, Alessandra
Franzin, Rossana
Sallustio, Fabio
Divella, Chiara
Spinelli, Alessandra
Netti, Giuseppe Stefano
Fiaccadori, Enrico
Cantaluppi, Vincenzo
Crovace, Antonio
Staffieri, Francesco
Lacitignola, Luca
Grandaliano, Giuseppe
Simone, Simona
Pertosa, Giovanni Battista
Gesualdo, Loreto
LPS-Binding Protein Modulates Acute Renal Fibrosis by Inducing Pericyte-to-Myofibroblast Trans-Differentiation through TLR-4 Signaling
title LPS-Binding Protein Modulates Acute Renal Fibrosis by Inducing Pericyte-to-Myofibroblast Trans-Differentiation through TLR-4 Signaling
title_full LPS-Binding Protein Modulates Acute Renal Fibrosis by Inducing Pericyte-to-Myofibroblast Trans-Differentiation through TLR-4 Signaling
title_fullStr LPS-Binding Protein Modulates Acute Renal Fibrosis by Inducing Pericyte-to-Myofibroblast Trans-Differentiation through TLR-4 Signaling
title_full_unstemmed LPS-Binding Protein Modulates Acute Renal Fibrosis by Inducing Pericyte-to-Myofibroblast Trans-Differentiation through TLR-4 Signaling
title_short LPS-Binding Protein Modulates Acute Renal Fibrosis by Inducing Pericyte-to-Myofibroblast Trans-Differentiation through TLR-4 Signaling
title_sort lps-binding protein modulates acute renal fibrosis by inducing pericyte-to-myofibroblast trans-differentiation through tlr-4 signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696277/
https://www.ncbi.nlm.nih.gov/pubmed/31357597
http://dx.doi.org/10.3390/ijms20153682
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