LPS-binding protein modulates acute renal fibrosis by inducing pericyte-to-myofibroblast trans-differentiation through TLR-4 signaling

Giuseppe Grandaliano, Giuseppe Castellano, Alessandra Stasi, Rossana Franzin, Fabio Sallustio, Chiara Divella, Alessandra Spinelli, Giuseppe Stefano Netti, Enrico Fiaccadori, Vincenzo Cantaluppi, Antonio Crovace, Francesco Staffieri, Luca Lacitignola, Simona Simone, Giovanni Battista Pertosa, Loreto Gesualdo

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

10 Citazioni (Scopus)

Abstract

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.
Lingua originaleEnglish
pagine (da-a)3682-3690
Numero di pagine9
RivistaInternational Journal of Molecular Sciences
Volume20
DOI
Stato di pubblicazionePubblicato - 2019

Keywords

  • Acute Kidney Injury
  • Acute-Phase Proteins
  • Animals
  • Biopsy
  • Carrier Proteins
  • Cell Transdifferentiation
  • Cells, Cultured
  • Disease Models, Animal
  • Endotoxemia-induced oliguric kidney injury
  • Endotoxins
  • Fibrosis
  • Immunohistochemistry
  • LPS-binding protein
  • Membrane Glycoproteins
  • Models, Biological
  • Myofibroblast
  • Myofibroblasts
  • Pericyte
  • Pericytes
  • Swine
  • Toll-Like Receptor 4

Fingerprint Entra nei temi di ricerca di 'LPS-binding protein modulates acute renal fibrosis by inducing pericyte-to-myofibroblast trans-differentiation through TLR-4 signaling'. Insieme formano una fingerprint unica.

Cita questo