Peritubular capillary dysfunction and renal tubular epithelial cell stress following lipopolysaccharide administration in mice.
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 (r(2) = 0.8951, P < 0.0001). These data show that peritubular capillary dysfunction is an early event that contributes to tubular stress and renal injury.
Wu
Liping
L
Dept. of Pharmacology and Toxicology, Univ. of Arkansas for Medical Sciences, 4301 West Markham St., #611, Little Rock, AR 72205, USA.
Tiwari
Manish M
MM
Messer
Kurt J
KJ
Holthoff
Joseph H
JH
Gokden
Neriman
N
Brock
Robert W
RW
Mayeux
Philip R
PR
D000818:Animals; D001806:Blood Urea Nitrogen; D015153:Blotting, Western; D002196:Capillaries / Q000502:physiology; D003404:Creatinine / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000139:chemically induced / Q000503:physiopathology*; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018715:Microscopy, Video; D009249:NADP / Q000378:metabolism; D009566:Nitrates / Q000097:blood; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D009573:Nitrites / Q000097:blood; D051437:Renal Insufficiency / Q000139:chemically induced / Q000503:physiopathology; D013312:Stress, Physiological / Q000503:physiopathology
D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D009249:NADP; D003404:Creatinine; D052247:Nitric Oxide Synthase Type II