Role of collecting duct endothelin in control of renal function and blood pressure

Abstract

Over 26,000 manuscripts have been published dealing with endothelins since their discovery 25 years ago. These peptides, and particularly endothelin-1 (ET-1), are expressed by, bind to, and act on virtually every cell type in the body, influencing multiple biological functions. Among these actions, the effects of ET-1 on arterial pressure and volume homeostasis have been most extensively studied. While ET-1 modulates arterial pressure through regulation of multiple organ systems, the peptide's actions in the kidney in general, and the collecting duct in particular, are of unique importance. The collecting duct produces large amounts of ET-1 that bind in an autocrine manner to endothelin A and B receptors, causing inhibition of Na(+) and water reabsorption; absence of collecting duct ET-1 or its receptors is associated with marked salt-sensitive hypertension. Collecting duct ET-1 production is stimulated by Na(+) and water loading through local mechanisms that include sensing of salt and other solute delivery as well as shear stress. Thus the collecting duct ET-1 system exists, at least in part, to detect alterations in, and maintain homeostasis for, extracellular fluid volume. Derangements in collecting duct ET-1 production may contribute to the pathogenesis of genetic hypertension. Blockade of endothelin receptors causes fluid retention due, in large part, to inhibition of the action of ET-1 in the collecting duct; this side effect has substantially limited the clinical utility of this class of drugs. Herein, the biology of the collecting duct ET-1 system is reviewed, with particular emphasis on key issues and questions that need addressing.

Salt control. Focus on “High salt induces autocrine actions of ET-1 on inner medullary collecting duct NO production via upregulated ETB receptor expression”

“…Accordingly, a multitude of regulatory systems exist-both locally within the kidney and systemically within the entire organism-regulating the ingestion and renal excretion of sodium-both with and without involvement of pressure natriuresis, and thus with and without salt-sensitive hypertension (4). One of these sodium regulatory systems is provided by ET-1 in the inner medulla of the kidney in close interaction with NO (8,(16)(17)(18)(19)30).…”

“…However, they are also expressed in many other tissues, including the kidney and, particularly, the renal inner medulla (19,30). Here, endothelins are produced in both endothelial and tubular cells (16,18,19). Endothelins act via two G protein-coupled receptors, ET A and ET B receptors (19,25).…”

“…The diuresis induced by a challenge with free water and the natriuresis after a load of sodium are both associated with enhanced excretion rate of ET-1 in the urine (reviewed in Ref. 18), although in a study on humans, small acute sodium loads failed to affect urinary ET-1 excretion (3). Similarly, sodium loading leads to enhanced urinary excretion of NO-metabolites (reviewed in Ref.…”

“…the macula densa (23). Sodium reabsorption in the IMCD is mediated primarily via the epithelial sodium channel (ENaC) (29,34), and ET-1 inhibits the open probability of ENaC (2,16,18,30). In the collecting duct, this effect is mediated primarily via ET B receptors (5) and involves signal transduction via src kinase and MAPK1/2 (6).…”

Endothelines and Cardiovascular Pathology

“…Таким образом, определение уровня эндотелина и его предшественника на сегодняшний день явля-ется надежным скрининговым тестом для диагно-стики ХСН, стратификации риска развития ХСН и ее прогноза [41][42][43][44][45].…”