Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease
Nathalie Sabaa, Lucia de Franceschi, Philippe Bonnin, Yves Castier, Giorgio Malpeli, Haythem Debbabi, Ariane Galaup, Micheline Maier-Redelsperger, Sophie Vandermeersch, Aldo Scarpa, Anne Janin, Bernard Levy, Robert Girot, Yves Beuzard, Christophe Leboeuf, Annie Henri, Stéphane Germain, Jean-Claude Dussaule, Pierre-Louis Tharaux
Nathalie Sabaa, Lucia de Franceschi, Philippe Bonnin, Yves Castier, Giorgio Malpeli, Haythem Debbabi, Ariane Galaup, Micheline Maier-Redelsperger, Sophie Vandermeersch, Aldo Scarpa, Anne Janin, Bernard Levy, Robert Girot, Yves Beuzard, Christophe Leboeuf, Annie Henri, Stéphane Germain, Jean-Claude Dussaule, Pierre-Louis Tharaux
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Research Article Nephrology

Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease

Abstract

Patients with sickle-cell disease (SCD) suffer from tissue damage and life-threatening complications caused by vasoocclusive crisis (VOC). Endothelin receptors (ETRs) are mediators of one of the most potent vasoconstrictor pathways in mammals, but the relationship between vasoconstriction and VOC is not well understood. We report here that pharmacological inhibition of ETRs prevented hypoxia-induced acute VOC and organ damage in a mouse model of SCD. An in vivo ultrasonographic study of renal hemodynamics showed a substantial increase in endothelin-mediated vascular resistance during hypoxia/reoxygenation-induced VOC. This increase was reversed by administration of the dual ETR antagonist (ETRA) bosentan, which had pleiotropic beneficial effects in vivo. It prevented renal and pulmonary microvascular congestion, systemic inflammation, dense rbc formation, and infiltration of activated neutrophils into tissues with subsequent nitrative stress. Bosentan also prevented death of sickle-cell mice exposed to a severe hypoxic challenge. These findings in mice suggest that ETRA could be a potential new therapy for SCD, as it may prevent acute VOC and limit organ damage in sickle-cell patients.

Authors

Nathalie Sabaa, Lucia de Franceschi, Philippe Bonnin, Yves Castier, Giorgio Malpeli, Haythem Debbabi, Ariane Galaup, Micheline Maier-Redelsperger, Sophie Vandermeersch, Aldo Scarpa, Anne Janin, Bernard Levy, Robert Girot, Yves Beuzard, Christophe Leboeuf, Annie Henri, Stéphane Germain, Jean-Claude Dussaule, Pierre-Louis Tharaux

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Figure 6

Bosentan prevents increased renal and lung MPO activity, peroxynitrite-induced protein tyrosine nitration in the kidneys, and severe hypoxia–induced death.

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Bosentan prevents increased renal and lung MPO activity, peroxynitrite-i...
MPO activity in (A) kidneys and (B) lungs of WT and SAD mice at steady state and after 18-hour exposure to H/R. *P < 0.05 vs. SAD at steady state; #P < 0.05 vs. SAD in H/R. (C–H) Anti-nitrotyrosine staining of kidney sections is strong in SAD mice in the (E) renal cortex and, to an even greater extent, in the (G) renal medulla under H/R conditions. (F and H) Bosentan administration before H/R prevented protein tyrosine nitration in these 2 renal compartments. Original magnification, ×100. (I) Endothelin receptor antagonism with bosentan protects SAD mice from death due to severe VOC after exposure to a 6% O2 atmosphere for 10 hours. Survival curves for vehicle-treated SAD mice are significantly different (P < 0.001) from those for bosentan-treated SAD mice and WT controls. n = 8–12 mice per group.