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Am J Physiol Renal Physiol 292: F261-F268, 2007. First published August 22, 2006; doi:10.1152/ajprenal.00263.2006
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Peritubular capillary dysfunction and renal tubular epithelial cell stress following lipopolysaccharide administration in mice

Departments of ¹Pharmacology and Toxicology and ²Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas

Submitted 11 July 2006 ; accepted in final form 15 August 2006

The mortality rate for septic patients with acute renal failure is extremely high. Since sepsis is often caused by lipopolysaccharide (LPS), a model of LPS challenge was used to study the development of kidney injury. Intravital video microscopy was utilized to investigate renal peritubular capillary blood flow in anesthetized male C57BL/6 mice at 0, 2, 6, 10, 18, 24, 36, and 48 h after LPS administration (10 mg/kg ip). As early as 2 h, capillary perfusion was dramatically compromised. Vessels with continuous flow were decreased from 89 ± 4% in saline controls to 57 ± 5% in LPS-treated mice (P < 0.01), and vessels with intermittent flow were increased from 6 ± 2% to 31 ± 5% (P < 0.01). At 2 h, mRNA for intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were elevated 50- and 27-fold, respectively, suggesting that vascular inflammation is an early event that may contribute to capillary dysfunction. By 10 h, vessels with no flow increased from 5 ± 2% in saline controls to 19 ± 3% in LPS-treated mice (P < 0.05). By 48 h, capillary function was returning toward control levels. The decline in functional capillaries preceded the development of renal failure and was paralleled by induction of inducible nitric oxide synthase in the kidney. Using NAD(P)H autofluorescence as an indicator of cellular redox stress, we found that tubular cell stress was highly correlated with the percentage of dysfunctional capillaries (r² = 0.8951, P < 0.0001). These data show that peritubular capillary dysfunction is an early event that contributes to tubular stress and renal injury.

intravital video microscopy; sepsis; inducible nitric oxide synthase; intercellular adhesion molecule-1; vascular cell adhesion molecule-1

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