title: Shock-induced stress induces loss of microvascular endothelial Tie2 in the kidney which is not associated with reduced glomerular barrier function.
abstract: Both hemorrhagic shock and endotoxemia induce a pronounced vascular activation in the kidney which coincides with albuminuria and glomerular barrier dysfunction. We hypothesized that changes in Tie2, a vascular restricted receptor tyrosine kinase shown to control microvascular integrity and endothelial inflammation, underlie this loss of glomerular barrier function. In healthy murine and human kidney, Tie2 is heterogeneously expressed in all microvascular beds, although to different extents. In mice subjected to hemorrhagic and septic shock, Tie2 mRNA and protein were rapidly, and temporarily, lost from the renal microvasculature, and normalized within 24 h after initiation of the shock insult. The loss of Tie2 protein could not be attributed to shedding as both in mice and healthy volunteers subjected to endotoxemia, sTie2 levels in the systemic circulation did not change. In an attempt to identify the molecular control of Tie2, we activated glomerular endothelial cell cultures and human kidney slices in vitro with LPS or TNF-alpha, but did not observe a change in Tie2 mRNA levels. In parallel to the loss of Tie2 in vivo, an overt influx of neutrophils in the glomerular compartment, which coincided with proteinuria, was seen. As neutrophil-endothelial cell interactions may play a role in endothelial adaptation to shock, and these effects cannot be mimicked in vitro, we depleted neutrophils before shock induction. While this neutrophil depletion abolished proteinuria, Tie2 was not rescued, implying that Tie2 may not be a major factor controlling maintenance of the glomerular filtration barrier in this model.
authors.affiliation: Medical Biology Section, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Matijs
authors.initials: M
authors.lastname: van Meurs
authors.forename: Neng F
authors.initials: NF
authors.lastname: Kurniati
authors.forename: Francis M
authors.initials: FM
authors.lastname: Wulfert
authors.forename: Sigridur A
authors.initials: SA
authors.lastname: Asgeirsdottir
authors.forename: Inge A
authors.initials: IA
authors.lastname: de Graaf
authors.forename: Simon C
authors.initials: SC
authors.lastname: Satchell
authors.forename: Peter W
authors.initials: PW
authors.lastname: Mathieson
authors.forename: Rianne M
authors.initials: RM
authors.lastname: Jongman
authors.forename: Philipp
authors.initials: P
authors.lastname: Kümpers
authors.forename: Jan G
authors.initials: JG
authors.lastname: Zijlstra
authors.forename: Peter
authors.initials: P
authors.lastname: Heeringa
authors.forename: Grietje
authors.initials: G
authors.lastname: Molema
mesh_terms: D000368:Aged; D000419:Albuminuria / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002199:Capillary Permeability; D002460:Cell Line; D004195:Disease Models, Animal; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D005919:Glomerular Filtration Rate; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000098:blood supply / Q000378:metabolism* / Q000503:physiopathology; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000378:metabolism; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism*; D012771:Shock, Hemorrhagic / Q000378:metabolism* / Q000503:physiopathology; D012772:Shock, Septic / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C433788:lipopolysaccharide, E. coli O26-B6; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse