Endothelin Modulation of Renal Sodium and Water Transport
Less than a decade ago, endothelin-1 (ET-1) was identified as the most potent vasoconstrictor known.1 With this discovery, the scientific medical community, both academic and industrial, launched a massive attempt to implicate ET-1 in the pathogenesis of
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Endothelin Modulation of Renal Sodium and Water Transport Donald E. Kohan
Introduction
L
ess than a decade ago, endothelin-1 (ET-1) was identified as the most potent vasoconstrictor known. l With this discovery, the scientific medical community, both academic and industrial, launched a massive attempt to implicate ET-1 in the pathogenesis of disorders associated with elevated vascular tone, including hypertension, atherosclerosis, myocardial infarction, pulmonary hypertension, and cerebrovascular accident. As a result, some clinical situations were identified in which ET-1 blockade may be therapeutic (e.g. acute renal failure), however, many other diseases (such as essential hyPertension) did not appear to be primarily mediated by dysregulated ET-1 activity. During this rush to understand and treat vascular disorders associated with altered ET-1 effects, it became increasingly evident that the biology of endothelin was far more complex than originally suspected. Where we once thought ET-1 was primarily an endothelial cell-derived product (hence its name), we now know that ET-1 is actually a family of peptides that are produced by a tremendous variety of cell types. Furthermore, ET-1 has a broad spectrum of biological actions affecting multiple cell types, many of which are nonvascular. Our laboratory first became interested in one of these nonvascular sites in 1989 when we heard a report describing the distribution of immunoreactive ET-1 in the body.2 This study determined that of all tissues in the body (using the pig as a model), the inner medulla of the kidney had by far the greatest concentration of ET-1. Why would this potent vasoconstrictor be expressed in such high amounts in a region virtually devoid of vascular smooth muscle? Part of the answer was suggested by another report about that time which described ET-1 inhibition of Na+/K+ ATPase activity in the inner medullary collecting duct (IMCD).3 Could it be that ET-1 was produced by cells in the inner medulla and then acted locally to regulate collecting duct sodium transport? If so, could ET-1 regulation of renal tubule sodium reabsorption somehow be related to the vascular actions of the peptide? So began a large number of studies by our laboratory and many others into the role of ET-1 in modulating renal tubule transport processes. These investigations have revealed a highly complex system whereby ET-1 potently modulates solute and water transport systems throughout the nephron. This chapter will review much
Endothelin Receptors and Signaling Mechanisms, edited by David M. Pollock
and Robert F. Highsmith. © 1998 Springer-Verlag and R.G. Landes Company.
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Endothelin Receptors and Signaling Mechanisms
of the work leading to our current understanding of ET-l regulation of renal tubule water and electrolyte transport. In addition, the relevance of this system to fluid and electrolyte homeostasis will be discussed.
Endothelin Regulation of Water and Electrolyte Transport
Before discussing ET-l regulation of nephron transport processes, it is use
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