Protective role of nitric oxide in mice with Shiga toxin-induced hemolytic uremic syndrome.
BACKGROUND
Nitric oxide (NO) is an endogenous vasodilator and platelet inhibitor. An enhanced NO production has been detected in patients with hemolytic uremic syndrome (HUS), although its implication in HUS pathogenesis has not been clarified.


METHODS
A mouse model of Shiga toxin 2 (Stx2)-induced HUS was used to study the role of NO in the development of the disease. Modulation of l-arginine-NO pathway was achieved by oral administration of NO synthase (NOS) substrate or inhibitors, and renal damage, mortality and platelet activity were evaluated. The involvement of platelets was studied by means of a specific anti-platelet antibody.


RESULTS
Inhibition of NO generation by the NOS inhibitor L-NAME enhanced Stx2-mediated renal damage and lethality; this effect was prevented by the addition of l-arginine. The worsening effect of L-NAME involved enhanced Stx2-mediated platelet activation, and it was completely prevented by platelet depletion.


CONCLUSIONS
NO exerts a protective role in the early pathogenesis of HUS, and its inhibition potentiates renal damage and mortality through a mechanism involving enhanced platelet activation.
Dran
Graciela I
GI
División Medicina Experimental, Departamento de Hemostasia y Trombosis, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Pacheco de Melo 3081, 1425 Capital Federal, Buenos Aires, Republica Argentina. colodran@hotmail.com
Fernández
Gabriela C
GC
Rubel
Carolina J
CJ
Bermejo
Emilse
E
Gomez
Sonia
S
Meiss
Roberto
R
Isturiz
Martín A
MA
Palermo
Marina S
MS
D000818:Animals; D015550:Cell Degranulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005340:Fibrinogen / Q000032:analysis; D006463:Hemolytic-Uremic Syndrome / Q000139:chemically induced / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D015539:Platelet Activation / Q000187:drug effects; D022641:Shiga Toxin 2 / Q000633:toxicity*; D013927:Thrombosis / Q000139:chemically induced / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D014508:Urea / Q000097:blood
D004791:Enzyme Inhibitors; D022641:Shiga Toxin 2; D009569:Nitric Oxide; D014508:Urea; D005340:Fibrinogen; D019331:NG-Nitroarginine Methyl Ester