Reduced nitric oxide bioavailability in a baboon model of Shiga toxin mediated hemolytic uremic syndrome (HUS).
BACKGROUND
Although there is agreement that post-diarrheal hemolytic uremic syndrome (D+ HUS) is caused by Shiga toxin (Stx)-producing E. coli, little is known about factors that mediate the host response to these toxins and potentially contribute to pathogenesis. Nitric oxide (NO) is a candidate mediator by virtue of its antiplatelet and renal vasodilatory properties.


METHODS
We used a baboon model of HUS to measure plasma and urinary NO metabolites and expression of NO synthase (eNOS and iNOS) in renal tissue following the intravenous administration of Stx-1.


RESULTS
Plasma concentrations through 60 hours of observation did not differ significantly from controls. Urinary values (indexed against urinary creatinine) tended, however, to rise during the initial 12 hours following administration of Stx-1. This was followed by a sustained reduction that coincided with the development of hemolytic anemia (schistocytosis) and other features of HUS. However, immunohistochemical staining for eNOS and iNOS in tissue obtained immediately after death at a median of 59 hours showed similar levels in control and Stx-treated animals, despite the presence of a florid thrombotic microangiopathy and tubular injury in the Stx-treated group.


CONCLUSIONS
We propose that urinary NO metabolite reduction was due to NO inactivation subsequent to its avid binding to free hemoglobin released from lysed red blood cells, and that this contributed to the acute renal failure by facilitating vasoconstriction and platelet aggregation and adhesion within the renal microvasculature.
Siegler
Richard L
RL
Division of Nephrology and Hypertension, Department of Pediatrics, University School of Medicine, 30 N 1900 E #2B422, Salt Lake City, UT 84132, USA. dick.siegler@hsc.utah.edu
Pysher
Theodore J
TJ
Tesh
Vernon L
VL
Noris
Marina
M
Cassis
Paola
P
Taylor
Fletcher B
FB
D000818:Animals; D001774:Blood Chemical Analysis; D004195:Disease Models, Animal; D006463:Hemolytic-Uremic Syndrome / Q000201:enzymology* / Q000503:physiopathology*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000378:metabolism*; D010215:Papio; D012016:Reference Values; D012307:Risk Factors; D012680:Sensitivity and Specificity; D022621:Shiga Toxin; D016482:Urinalysis
D009569:Nitric Oxide; D022621:Shiga Toxin; D019001:Nitric Oxide Synthase