Age-dependent role of microvascular endothelial and polymorphonuclear cells in lipopolysaccharide-induced acute kidney injury.
BACKGROUND
The incidence of acute kidney injury following severe sepsis is higher in the elderly. We hypothesized that microvascular endothelium is "primed" by aging and that sepsis represents a "second hit," resulting in more severe microvascular complications.


METHODS
Three- and 18-months-old mice were intraperitoneally injected with 1,500 EU/g body weight lipopolysaccharide and sacrificed after 8 h. Flow cytometry and myeloperoxidase ELISA determined neutrophils in plasma. Quantitative reverse transcription polymerase chain reaction was used to analyze messenger ribonucleic acid levels of cell adhesion molecules P-selectin and E-selectin, vascular cell adhesion protein-1, intercellular adhesion molecule-1, angiopoietin receptor TIE-2, and angiopoietins Ang1 and Ang2. In kidney tissue we assessed neutrophil influx and E-selectin protein expression. Neutrophils were depleted with the monoclonal antibody NIMP.


RESULTS
At basal conditions, microvascular endothelial cell activation status was similar in both groups, except for a higher Ang-2 expression (P < 0.05) in the kidney of aged mice. Lipopolysaccharide-induced increase in neutrophil count was higher in old (3.3-fold change) compared with young mice (2.2-fold change). Messenger ribonucleic acid analysis showed higher upregulation of P- and E-selectin (P = 0.0004, P = 0.0007) after lipopolysaccharide administration in kidneys of elderly mice, which was confirmed at the protein level for E-selectin. Renal neutrophil influx in lipopolysaccharide-treated aged mice was increased (2.5-fold induction in aged and 2.1-fold in young, P < 0.0001). Polymorphonuclear cell depletion exaggerated the lipopolysaccharide-induced kidney injury.


CONCLUSIONS
Ang-2 is increased in older mice, which might cause priming of the endothelial cells. Endothelium responded by a more extensive increase in expression of P- and E-selectin in older mice and increased polymorphonuclear cell influx.
Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Francis M
FM
Wulfert
Matijs
M
van Meurs
Neng F
NF
Kurniati
Rianne M
RM
Jongman
Martin C
MC
Houwertjes
Peter
P
Heeringa
Michel M R F
MM
Struys
Jan G
JG
Zijlstra
Grietje
G
Molema
D058186:Acute Kidney Injury / Q000139:chemically induced*; D000367:Age Factors; D042702:Angiopoietin-2 / Q000235:genetics; D000818:Animals; D019040:E-Selectin / Q000032:analysis; D042783:Endothelial Cells / Q000502:physiology*; D005260:Female; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000502:physiology; D009504:Neutrophils / Q000502:physiology*; D019007:P-Selectin / Q000032:analysis; D042787:Receptor, TIE-2 / Q000235:genetics
D042702:Angiopoietin-2; D019040:E-Selectin; D008070:Lipopolysaccharides; D019007:P-Selectin; D042787:Receptor, TIE-2