Endothelin receptors, renal effects and blood pressure

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Highlights

  • The endothelin system is a critical renal regulator of salt and water homeostasis.

  • Renal ETB receptor function is impaired in hypertensive males.

  • Endothelin increases glomerular permeability to albumin and injures podocytes.

  • Evidence implicates ETA receptor activation in chronic kidney disease progression.

  • Clinical use of ETA receptor antagonists still holds promise despite some setbacks.

The endothelin system has emerged as a key player in the renal control of salt and water homeostasis, exerting profound effects on both the renal vasculature and tubular epithelial cells. Recent advances include new actions of endothelins in the glomerulus, an emerging role for the ETA receptor in chronic kidney disease (CKD) progression and in tubular function, and a more detailed understanding of the tubular response to high salt intake. A large body of evidence also implicates dysfunction of the endothelin system in hypertension, particularly salt-sensitive hypertension, although recent data suggests important sex-differences may exist. Finally, clinical trials indicate that antagonists of endothelin receptors hold great promise in treating resistant hypertension and proteinuric renal disease.

Introduction

The endothelin system has a profound influence on both renal vascular and tubular function, and has emerged as a key player in the control of salt and water handling. In addition to endothelial cells, from which endothelin-1 (ET-1) was originally isolated [1], most cell types within the kidney produce and bind ET-1, with renal tubular epithelial cells, particularly of the inner medullary collecting duct, of major importance [2]. Of the three endothelin peptides (ET-1, ET-2 and ET-3), ET-1 is generally regarded as the main circulating isoform and has been the most extensively studied. However, it should be noted that both ET-1 and ET-3 are produced by tubular cells and could contribute to the intrarenal actions of the endothelin system [2]. Data on ET-2 expression are less extensive, but at least at the mRNA level, ET-2 appears to be present in the kidneys of most species. Release of endothelins from polarized cells is abluminal [3], emphasizing the importance of this system as a paracrine/autocrine modulator of renal function.

Endothelins act via two G-protein coupled receptors, ETA and ETB, which are highly expressed in the kidney. Expression of ETB receptors predominates in tubular epithelial cells and is generally thought to be the only endothelin receptor expressed by the endothelium, whereas renal vascular smooth muscle expresses both ETA and ETB receptors. The ETA receptor binds ET-1  ET-2  ET-3, and the ETB receptor binds all three peptides with similarly high affinity. These receptors engage multiple intracellular signaling pathways in a cell type-specific manner; the reader is directed to [4, 5] for recent, in-depth reviews. Briefly, both ETA and ETB receptors on vascular smooth muscle cells increase intracellular Ca2+ concentration and cause vasoconstriction, which is the dominant effect of ET-1 in most vascular beds. Endothelial ETB receptors contribute a vasodilatory influence via production of nitric oxide (NO) and vasodilator prostanoids and eicosanoids. The ETB receptor also serves as a ‘clearance’ receptor for endothelins [6], mediating their internalization and degradation. Accordingly, pharmacological blockade or dysfunction of the ETB receptor increases availability of endothelins for binding to the ETA receptor. The mediators elaborated by ETB receptors located on tubular epithelial cells show similarities to those released by endothelial cells, however as discussed below, additional signaling pathways are also employed with the net effect typically being inhibition of salt and water reabsorption. Both ET-1 production and receptor densities are higher in the renal medulla than cortex, with ETB receptors predominating, although the reported ratios of ETA to ETB receptors differ between species [4].

The role of endothelin in blood pressure and salt homeostasis was elegantly and exhaustively reviewed by Kohan and colleagues in 2011 [4]. Accordingly, this brief review will highlight some of the post-2011 advances in our understanding of the renal effects of endothelins, describe involvement of the intrarenal endothelin system in hypertension and the clinical potential for endothelin receptor antagonists (ERAs) in treating hypertension.

Section snippets

ET-1 is a powerful renal vasoconstrictor

ET-1 was first recognized as a powerful vasoconstrictor [1] and the renal vasculature is exquisitely sensitive to its actions [7]. Notably, renal vasoconstriction in response to ET-1 is unusually long-lasting compared to other vasoconstrictors such as angiotensin II, which produces transient reductions in renal blood flow when administered as a bolus. Essentially irreversible binding of ET-1 to its receptors has been proposed as a possible explanation, but a recent study reported that ET-1

ET-1 in the glomerulus

Glomerular expression of ET-1 increases in a variety of renal diseases. In addition to promoting mesangial cell proliferation and the ability to alter GFR through actions on pre-glomerular and post-glomerular microvessels [4], recent studies show that ET-1 via the ETA receptor directly increases glomerular permeability to albumin. This has been demonstrated using isolated glomeruli ex vivo [15], and using two-photon microscopy in vivo [16]. Two-photon microscopy also revealed that the filtered

Endothelin in the progression of renal injury

In addition to mediating glomerular injury, endothelins, predominantly acting via the ETA receptor, have further been implicated in damage of the renal parenchyma leading to progression to chronic kidney disease (CKD). In a swine model of renovascular disease, ETA receptor blockade has now been shown to largely prevent [20] or reverse [21] microvascular rarefaction, fibrosis and atrophy of the stenotic kidney, and improve renal perfusion and function. These findings were recently extended to

Endothelin promotes diuresis and natriuresis  a key response to high salt intake

The predominant tubular effect of endothelins is to oppose salt and water reabsorption, promoting diuresis and natriuresis [4]. The collecting duct is a key site for this effect, demonstrated by the sodium retention and salt-sensitivity of blood pressure resulting from conditional deletion of ET-1 from collecting duct principal cells [24]. Deletion of ETB receptors from principal cells also promotes salt-sensitive hypertension, albeit not to the full extent seen with deletion of ET-1 [25]. This

Emerging evidence for a role for ETA receptors in tubular function

Recent studies indicate that the ETA receptor also plays a role in renal salt and water handling, contributing to the phenomenon of fluid retention seen in patients treated with ETA receptor antagonists. Tubular ETA receptor expression is low relative to the ETB receptor, but there is evidence of ETA receptor expression in the proximal tubule and collecting duct [4]. A recent study demonstrated that ETA receptors can contribute to the inhibitory effect of ET-1 on ENaC activity and sodium

The ‘clock’ is ticking for endothelin

The importance of diurnal variation in blood pressure, highlighted by the enhanced risk of cardiovascular disease seen with so-called ‘non-dipping’ of night-time blood pressure, is now well-established. There is also growing evidence than many aspects of renal function also display circadian oscillations. Recent studies have begun to provide insights into the molecular mechanisms driving these diurnal rhythms, referred to as the circadian clock, and the endothelin system has been shown to fall

Endothelin as a player in hypertension

Soon after its discovery, interest rapidly turned to whether ET-1 contributes to hypertension. We now know that blockade of the ETA receptor or both ETA and ETB receptors reduces blood pressure in hypertensive humans [50, 51, 52, 53] and attenuates or abolishes hypertension in multiple animal models including angiotensin II infusion [54, 55, 56], Dahl Salt-sensitive rats [57] and DOCA-salt hypertension [58, 59, 60], as well as in other diseases such as preeclampsia [61] and systemic lupus

Clinical perspectives on the use of ERAs in hypertension

Clinical studies in hypertensive patients show that ERAs, of either the combined ETA and ETB variety (bosentan) [51] or more ETA receptor-selective agents (darusentan) [52], provide comparable efficacy in lowering blood pressure to agents targeting the renin angiotensin system. ERAs also reduce blood pressure in patients with CKD [53, 70] or type 2 diabetic nephropathy [85], and a combined endothelin-converting enzyme inhibitor and neutral endopeptidase inhibitor, daglutril, was recently shown

Conclusions

The role of the endothelin system in the physiological control of salt and water homeostasis, and evidence that dysregulation of this system can and does contribute to hypertension is now well-established. Additional evidence implicates ET-1 in promoting glomerular injury, proteinuria, and progression to CKD. Our understanding of the molecular mechanisms regulating expression of the endothelin system in health and disease continues to grow and now includes the circadian clock and epigenetics.

Future perspectives

Hypertension, diabetic nephropathy and CKD have rightly been prominent areas of interest in the endothelin field for many years. However, growth in the field and in the therapeutic application of ERAs may come from assessing or reassessing some of the less exhaustively studied diseases in which the endothelin system has been implicated. Many of these have proven difficult to treat effectively with currently available, non-ERA based therapies. For some, such as renovascular disease, clinical

Conflict of interest statement

The author currently receives research funding from Abbvie, Inc. to investigate the role of endothelin in acute renal failure. This has no bearing on the content of the current manuscript and as such does not pose a conflict of interest.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The author currently receives support for her research on the roles of endothelin in renal ischemia–reperfusion injury and in acute renal failure from the American Heart Association (12SDG8960028) and Abbvie, Inc., respectively.

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