Endothelin antagonists in hypertension and kidney disease
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EDUCATIONAL REVIEW
Endothelin antagonists in hypertension and kidney disease Kevin E. C. Meyers & Christine Sethna
Received: 12 July 2012 / Revised: 20 August 2012 / Accepted: 21 August 2012 / Published online: 16 October 2012 # IPNA 2012
Abstract The endothelin (ET) system seems to play a pivotal role in hypertension and in proteinuric kidney disease, including the micro- and macro-vascular complications of diabetes. Endothelin-1 (ET-1) is a multifunctional peptide that primarily acts as a potent vasoconstrictor with direct effects on systemic vasculature and the kidney. ET-1 and ET receptors are expressed in the vascular smooth muscle cells, endothelial cells, fibroblasts and macrophages in systemic vasculature and arterioles of the kidney, and are associated with collagen accumulation, inflammation, extracellular matrix remodeling, and renal fibrosis. Experimental evidence and recent clinical studies suggest that endothelin receptor blockade, in particular selective ETAR blockade, holds promise in the treatment of hypertension, proteinuria, and diabetes. Concomitant blockade of the ETB receptor is not usually beneficial and may lead to vasoconstriction and salt and water retention. The side-effect profile of ET receptor antagonists and relatively poor antagonist selectivity for ETA receptor are limitations that need to be addressed. This review will discuss what is currently known about the endothelin system, the role of ET-1 in the pathogenesis of hypertension and kidney disease, and summarize literature on the therapeutic potential of endothelin system antagonism.
K. E. C. Meyers (*) Nephrology Division, Department of Pediatrics, The Children’s Hospital of Philadelphia, 1st Floor Main Building, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA e-mail: [email protected] C. Sethna Division of Nephrology, Department of Pediatrics, Cohen Children’s Medical Center of New York, 269-01 76th Avenue, New Hyde Park, NY 11040, USA
Keywords Endothelin-1 . Endothelin-converting enzyme-1 . Endothelin A receptor . Endothelin B receptor . Chronic kidney disease
Introduction The main purpose of this review is to provide an overview of the endothelin system and its clinical relevance to hypertension and kidney disease. This review will approach the topic in two parts. In the basic science segment we will review the increasingly complex endothelin system with respect to the synthesis of endothelins, endothelin-converting enzymes, endothelin receptors, endothelin system antagonists, and the pathophysiology of endothelin in hypertension and renal disease. Of note, the major function of endothelin-1 (ET-1) is to act as a vasoconstrictor. However, it is much more than a vasoconstrictor, and as a multifunctional peptide with cytokine/hormone-like activity, ET-1 participates in a number of physiological activities, including mitogenesis, cell survival, angiogenesis, bone remodeling, epithelial to mesenchymal cell transition, and nociceptor stimulation; it also has a number of tumor-related activities. In the clinic
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