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 2

ETRA reverses and prevents the fall in renal blood flow velocity (RBF) in SAD mice.

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ETRA reverses and prevents the fall in renal blood flow velocity (RBF) i...
(A–C) Reversal of low renal perfusion in sickle mice by infusion of bosentan. Echo-Doppler measurements of (A) CO and (B) RBF velocity in the renal artery at steady state (white bars) and after H/R in SAD and WT mice before (black bars) and 10 minutes after infusion of bosentan (gray bars). H/R-induced vasoocclusive (VOC) events were associated with blunted CO and significant decreases in mean RBF velocity in SAD mice only. Acute infusion of bosentan restored 50% of the initial loss in RBF velocity within 10 minutes, whereas saline had no effect (not shown). n = 13. *P < 0.05 versus SAD at steady state; **P < 0.01 versus SAD at steady state; #P < 0.05 versus SAD before bosentan infusion. (C) Representative RBF waveforms in WT and SAD mice at steady state and after H/R followed by acute infusion of saline or bosentan. End-diastolic and time-averaged mean velocities were lower in saline-treated SAD mice after H/R than in normoxic WT and SAD mice. Acute ETRA restored end-diastolic and time-averaged mean velocities. (D and E) Prevention of H/R-induced renal hypoperfusion in SAD mice treated for 2 weeks with bosentan. (D) CO and (E) mean RBF velocity were unchanged in bosentan-treated SAD mice, whereas mean RBF velocity decreased by 50% in vehicle-treated SAD mice. All data are means ± SEM from n = 2 experiments. n > 10. ***P < 0.001 versus SAD at steady state; ##P < 0.01 versus vehicle-treated SAD in H/R.