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1 Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States; United States
2 Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
3 Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
* To whom correspondence should be addressed. E-mail: prmayeux{at}uams.edu.
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 kidney injury. Intravital videomicroscopy (IVVM) was utilized to investigate renal peritubular capillary blood flow in anesthetized male C57/BL6 mice at 0, 2, 6, 10, 18, 24, 36 and 48 h following LPS administration (10 mg/kg, i.p.). 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 < 0.001) and vessels with intermittent flow were increased from 6 ± 2% to 31 ± 5% (P < 0.01). At 2 h mRNA for ICAM-1 and VCAM-1 were elevated 50-fold and 27-fold respectively, suggesting 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 iNOS 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 = 0.8954; P < 0.001). These data show that peritubular capillary dysfunction is an early event that contributes to tubular stress and renal injury.
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