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 perm-selectivity. 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.

Reduction of Tubular Flow Rate as a Mechanism of Oliguria in the Early Phase of Endotoxemia Revealed by Intravital Imaging

“…42 Extrarenal TLR4 and increased TNF-a are associated with increased BUN and the progression of kidney damage after LPS injection in mice. [43][44][45] By contrast, we found no evidence that TNF-a contributes to the LPS-induced reduction in tubular flow rate. This discrepancy may result from differences in experimental settings, such as mouse age and strain, as well as LPS dosage.…”

Acute reactive oxygen species (ROS)-dependent effects of IL-1β, TNF-α, and IL-6 on the glomerular filtration barrier (GFB) in vivo

“…TNF-␣ has been shown, through its TNF receptor on renal endothelial cells, to cause acute kidney injury and structural changes in glomerular endothelial cells 24 h after the TNF-␣ injection. Alterations in the endothelial surface layer composition and decreased fenestral density, with enlargement of fenestral diameters and loss of fenestrae, have been demonstrated, with no major changes in podocyte morphology (58). Furthermore ROS infusion per se has been shown to cause dose-dependent transient proteinuria without ultrastructural abnormalities (60).…”

“…Studies of TNF-␣ action on isolated glomeruli in vitro have demonstrated an increased permeability of the glomerular filtration barrier (GFB) to albumin (at 15 min), mediated via the generation of reactive oxygen species (ROS) (36). Bertani et al (11) studied the effects of intravenous TNF-␣ infusion (0.8 -8 g·kg Ϫ1 ·h Ϫ1 ) on glomerular function and structure and found a dose-dependent glomerular endothelial cell "injury," although they did not show increases in proteinuria after 15 or 24 h. Recently, it was suggested that TNF-␣ (at a plasma concentration of 6.7 Ϯ 1.3 ng/ml) may mediate much of the actions of (bacterial) LPS on the glomerular endothelium and that TNF-␣ in mice can induce similar alterations as LPS when infused intravenously, contributing to an increased glomerular albumin permeability (58).…”

Necroinflammation in Kidney Disease

“…33,34 In turn, inflammation is an important accelerator of tubular injury 15, 85 and involves potential triggers of necroptosis such as TNF-a. 86,87 Oxalate crystal formation inside tubules induces RIPK3-and MLKL-dependent tubular cell death (S.R. Mulay and H.-J.…”