title: 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.
authors.affiliation: Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Fox
authors.affiliation: Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: mkasztan@uab.edu.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Kasztan
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications / Q000188:drug therapy*; D002908:Chronic Disease; D065128:Endothelin Receptor Antagonists / Q000627:therapeutic use*; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy / Q000209:etiology; D008171:Lung Diseases / Q000188:drug therapy / Q000209:etiology; D059408:Pain Management / Q000379:methods
chemical_list: D065128:Endothelin Receptor Antagonists
keywords: Endothelin-1; Nephropathy; Pain; Pulmonary hypertension; Sickle cell disease