title: Endothelial dysfunction and renal fibrosis in endotoxemia-induced oliguric kidney injury: possible role of LPS-binding protein.
abstract: BACKGROUND
  The pathophysiology of endotoxemia-induced acute kidney injury (AKI) is characterized by an intense activation of the host immune system and renal resident cells by lipopolysaccharide (LPS) and derived proinflammatory products. However, the occurrence of renal fibrosis in this setting has been poorly investigated. The aim of the present study was to investigate the possible association between endothelial dysfunction and acute development of tissue fibrosis in a swine model of LPS-induced AKI. Moreover, we studied the possible effects of coupled plasma filtration adsorption (CPFA) in this setting.
  
  
  METHODS
  After 9 hours from LPS infusion and 6 hours of CPFA treatment, histologic and biochemical changes were analyzed in pigs. Apoptosis and endothelial dysfunction were assessed on renal biopsies. The levels of LPS-binding protein (LBP) were quantified with enzyme-linked immunosorbent assay (ELISA). Endothelial cells (ECs) were stimulated in vitro with LPS and cultured in the presence of swine sera and were analyzed with FACS and real-time RT-PCR.
  
  
  RESULTS
  In a swine model of LPS-induced AKI, we observed that acute tubulointerstitial fibrosis occurred within 9 hours from LPS injection. Acute fibrosis was associated with dysfunctional alpha-smooth muscle actin (α-SMA)+ ECs characterized by active proliferation (Ki-67+) without apoptosis (caspase-3-). LPS led to EC dysfunction in vitro with significant vimentin and N-cadherin expression and increased collagen I mRNA synthesis. Therapeutic intervention by citrate-based CPFA significantly prevented acute fibrosis in endotoxemic animals, by preserving the EC phenotype in both peritubular capillaries and renal arteries. We found that the removal of LBP from plasma was crucial to eliminate the effects of LPS on EC dysfunction, by blocking LPS-induced collagen I production.
  
  
  CONCLUSIONS
  Our data indicate that EC dysfunction might be pivotal in the acute development of tubulointerstitial fibrosis in LPS-induced AKI. Selective removal of the LPS adaptor protein LBP might represent a future therapeutic option to prevent EC dysfunction and tissue fibrosis in endotoxemia-induced AKI.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Castellano
authors.forename: Alessandra
authors.initials: A
authors.lastname: Stasi
authors.forename: Angelica
authors.initials: A
authors.lastname: Intini
authors.forename: Margherita
authors.initials: M
authors.lastname: Gigante
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Di Palma
authors.forename: Chiara
authors.initials: C
authors.lastname: Divella
authors.forename: Giuseppe Stefano
authors.initials: GS
authors.lastname: Netti
authors.forename: Clelia
authors.initials: C
authors.lastname: Prattichizzo
authors.forename: Paola
authors.initials: P
authors.lastname: Pontrelli
authors.forename: Antonio
authors.initials: A
authors.lastname: Crovace
authors.forename: Francesco
authors.initials: F
authors.lastname: Staffieri
authors.forename: Enrico
authors.initials: E
authors.lastname: Fiaccadori
authors.forename: Nicola
authors.initials: N
authors.lastname: Brienza
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Grandaliano
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pertosa
authors.forename: Loreto
authors.initials: L
authors.lastname: Gesualdo
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000473:pathology*; D000209:Acute-Phase Proteins; D000818:Animals; D002352:Carrier Proteins; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005355:Fibrosis; D007668:Kidney / Q000098:blood supply / Q000473:pathology* / Q000503:physiopathology; D008562:Membrane Glycoproteins; D013552:Swine; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D053148:Caspase 3; D008562:Membrane Glycoproteins; D000099231:Lipopolysaccharide-Binding Protein