Endothelin receptor antagonists in sickle cell disease: A promising new therapeutic approach

Abstract

Sickle cell disease (SCD) is a genetic hematologic disorder that is characterized by a variety of potentially life threatening acute and chronic complications. Currently, hydroxyurea is the only clinically approved pharmacological therapy for the treatment of SCD, and the continued prevalence of severe disease complications underscores the desperate need for the development of new therapeutic agents. Central features of the sickle cell disease milieu, including hypoxia, oxidative stress, and thrombosis, are established enhancers of endothelin-1 (ET-1) synthesis. This conceptual connection between ET-1 and SCD was confirmed by multiple studies that demonstrated markedly elevated plasma and urinary levels of ET-1 in SCD patients. Direct evidence for the involvement of ET-1 signaling in the development of SCD pathologies has come from studies using endothelin receptor antagonists in SCD mice. This review summarizes recent studies that have implicated ET-1 signaling as a mechanistic contributor to renal, vascular, pulmonary, and nociceptive complications of sickle cell disease and discusses the potential for the use of ET receptor antagonists in the treatment of SCD.

Long-Term Endothelin-A Receptor Antagonism Provides Robust Renal Protection in Humanized Sickle Cell Disease Mice

“…16 ET-1 expression is induced by established hallmarks of the SCD milieu, including hypoxia, oxidative stress, and thrombosis. 17 This theoretic connection between SCD and ET-1 overproduction was validated by multiple studies that demonstrated elevated ET-1 levels in both plasma and urine of patients with SCD. 17 In the kidney, ET-1 has been implicated as a mechanistic contributor to development of proteinuria in various forms of CKD.…”

“…17 This theoretic connection between SCD and ET-1 overproduction was validated by multiple studies that demonstrated elevated ET-1 levels in both plasma and urine of patients with SCD. 17 In the kidney, ET-1 has been implicated as a mechanistic contributor to development of proteinuria in various forms of CKD. [18][19][20][21][22] Moreover, the elevated urinary ET-1 excretion reported in patients with SCD correlates with microalbuminuria, 23 suggesting a pathophysiologic link between ET-1 induction and renal injury in SCD.…”

Sickle Cell Nephropathy: Current Understanding of the Presentation, Diagnostic and Therapeutic Challenges

“…Bosentan, a dual ETA/ETB receptor antagonist used in murine models, decreases hypoxia-related injury to renal vessels and lung inflammation [26]. As it has been shown by Kasztan' s studies, administration of ambrisentan (an ETA receptor antagonist), at the time of weaning and continued for 10 weeks, prevented glomerular dysfunction, tubulointerstitial inflammation and fibrosis [24]. The observations of Kasztan et al support this speculation as the markedly elevated plasma ET-1 levels that occur in this model are normalized by chronic administration of ambrisentan [21].…”

“…It has also been shown that plasma ET-1 levels are elevated in patients with SCD during steady state periods as well as during acute vaso-occlusive crisis. Conversely, plasma ET-1 levels are decreased in SCD patients treated with hydroxyurea [24]. Elevated ET-1 level in SCD is associated with endothelial dysfunction and albuminuria in patients with SCD [25].…”

Endothelin-A Receptor Antagonism Retards the Progression of Murine Sickle Cell Nephropathy

“…5 Plasma ET-1 levels are elevated in patients with SCD in steady state and more so during crisis; plasma ET-1 levels decrease in patients treated with hydroxyurea, a therapy that reduces the frequency of vasoocclusive disease. 6 Both endothelial dysfunction and albuminuria in human SCD associate with plasma ET-1 levels. 7 Studies in a murine SCD model attest to the pathogenetic role of ET-1 in SCD by demonstrating that bosentan, a dual ET A /ET B receptor antagonist, attenuates renal vasoocclusion, vasoconstriction, and inflammation induced in this model by hypoxia/reoxygenation; bosentan also reduces vasoocclusion and inflammation in the lungs and mortality following such hypoxic stress.…”