title: TNF-mediated damage to glomerular endothelium is an important determinant of acute kidney injury in sepsis.
abstract: Severe sepsis is often accompanied by acute kidney injury (AKI) and albuminuria. Here we studied whether the AKI and albuminuria associated with lipopolysaccharide (LPS) treatment in mice reflects impairment of the glomerular endothelium with its associated endothelial surface layer. LPS treatment decreased the abundance of endothelial surface layer heparan sulfate proteoglycans and sialic acid, and led to albuminuria likely reflecting altered glomerular filtration permselectivity. LPS treatment decreased the glomerular filtration rate (GFR), while also causing significant ultrastructural alterations in the glomerular endothelium. The density of glomerular endothelial cell fenestrae was 5-fold lower, whereas the average fenestrae diameter was 3-fold higher in LPS-treated than in control mice. The effects of LPS on the glomerular endothelial surface layer, endothelial cell fenestrae, GFR, and albuminuria were diminished in TNF receptor 1 (TNFR1) knockout mice, suggesting that these LPS effects are mediated by TNF-α activation of TNFR1. Indeed, intravenous administration of TNF decreased GFR and led to loss of glomerular endothelial cell fenestrae, increased fenestrae diameter, and damage to the glomerular endothelial surface layer. LPS treatment decreased kidney expression of vascular endothelial growth factor (VEGF). Thus, our findings confirm the important role of glomerular endothelial injury, possibly by a decreased VEGF level, in the development and progression of AKI and albuminuria in the LPS model of sepsis in the mouse.
authors.affiliation: Section of Nephrology, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Chang
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Chang
authors.affiliation: Section of Nephrology, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Hack
authors.affiliation: Section of Nephrology, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Eadon
authors.affiliation: Renal Division and Molecular and Vascular Medicine Unit, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
authors.affiliation: Section of Nephrology, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Cunningham
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology*; D000419:Albuminuria / Q000209:etiology; D000818:Animals; D004195:Disease Models, Animal; D007678:Kidney Glomerulus / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D018805:Sepsis / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D019459:Urothelium / Q000503:physiopathology*
chemical_list: D008070:Lipopolysaccharides; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha
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