Endothelin synthesis and receptors in porcine kidney

American Journal of Physiology-Regulatory, Integrative and Comp

2013

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.

Section: Expression and Regulation Of Collecting Duct Et Receptorsmentioning

confidence: 92%

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

American Journal of Physiology-Regulatory, Integrative and Comp

2013

“…Descending vasa recta in the outer medulla express both ET A and ET B . In the porcine kidney, the relative ET A /ET B proportion averaged ~60/40 in glomerular membranes, but only ET B binding could be identified in papillary membrane preparations (25). Similar studies conducted using human tissues suggest that ~30% of the receptors expressed in both the renal cortex and medulla are of the ET A subtype (529).…”

Section: Endothelin and The Kidneymentioning

confidence: 99%

“…Metabolic labeling, immunohistochemical and radioimmunoassay analysis of ET levels, as well as RT-PCR of mRNA expression in microdissected nephron segments have repeatedly shown that the inner medullary CD (IMCD) produces more ET (primarily ET-1) than any other cell type in the nephron, at least in the rat and rabbit (97, 368, 787, 790). Similarly, porcine IMCD synthesize relatively high levels of ET-1 (25). These findings were further supported by in situ hybridization studies of human kidneys (598); in addition, ET-1 release and mRNA expression have been detected in cultured human IMCD cells (367).…”

Section: Endothelin and The Kidneymentioning

confidence: 99%

“…Porcine renal papillary membranes contained a single class of receptors with a K d of 137 pM; ET-1 binding was unaffected by BQ123, but completely blocked by bosentan (combined ET A/B blocker), suggesting that only ET B was present (25). Binding studies in microdissected rat CCD showed a single class of receptors with similar ET-1 and ET-1 binding, while specific ET B , but not ET A , antagonism blocked ET-1 binding (757).…”

Section: Endothelin and The Kidneymentioning

confidence: 99%

See 1 more Smart Citation

Regulation of Blood Pressure and Salt Homeostasis by Endothelin

Rossi

Inscho

et al. 2011

Physiological Reviews

373

459

Endothelin (ET) peptides and their receptors are intimately involved in the physiological control of systemic blood pressure and body Na homeostasis, exerting these effects through alterations in a host of circulating and local factors. Hormonal systems affected by ET include natriuretic peptides, aldosterone, catecholamines, and angiotensin. ET also directly regulates cardiac output, central and peripheral nervous system activity, renal Na and water excretion, systemic vascular resistance, and venous capacitance. ET regulation of these systems is often complex, sometimes involving opposing actions depending on which receptor isoform is activated, which cells are affected, and what other prevailing factors exist. A detailed understanding of this system is important; disordered regulation of the ET system is strongly associated with hypertension and dysregulated extracellular fluid volume homeostasis. In addition, ET receptor antagonists are being increasingly used for the treatment of a variety of diseases; while demonstrating benefit, these agents also have adverse effects on fluid retention that may substantially limit their clinical utility. This review provides a detailed analysis of how the ET system is involved in the control of blood pressure and Na homeostasis, focusing primarily on physiological regulation with some discussion of the role of the ET system in hypertension.

“…Descending vasa recta in the outer medulla express both ETA and ETB. The relative ETA/ETB proportion in porcine kidneys averages approximately 60/40 in glomerular membranes, but only ETB binding could be identified in papillary membranes (19). Approximately 30% of the receptors expressed in the human renal cortex and medulla are ETA (300).…”

Section: Et and The Renal Vasculaturementioning

confidence: 99%

Physiology of Endothelin and the Kidney

Comprehensive Physiology

Inscho

Wesson

et al. 2011

104

136

Since its discovery in 1988 as an endothelial cell-derived peptide that exerts the most potent vasoconstriction of any known endogenous compound, endothelin (ET) has emerged as an important regulator of renal physiology and pathophysiology. This review focuses on how the ET system impacts renal function in health; it is apparent that ET regulates multiple aspects of kidney function. These include modulation of glomerular filtration rate and renal blood flow, control of renin release, and regulation of transport of sodium, water, protons and bicarbonate. These effects are exerted through ET interactions with almost every cell type in the kidney, including mesangial cells, podocytes, endothelium, vascular smooth muscle, every section of the nephron, and renal nerves. In addition, while not the subject of the current review, ET can also indirectly affect renal function through modulation of extrarenal systems, including the vasculature, nervous system, adrenal gland, circulating hormones and the heart. As will become apparent, these pleiotropic effects of ET are of fundamental physiologic importance in the control of renal function in health. In addition, to help put these effects into perspective, we will also discuss, albeit to a relatively limited extent, how alterations in the ET system can contribute to hypertension and kidney disease.