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Cardiovascular Research 1998 39(3):543-549; doi:10.1016/S0008-6363(98)00155-2
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Copyright © 1998, European Society of Cardiology

Endothelin blockers and renal protection: a new strategy to prevent end-organ damage in cardiovascular disease?

Ton J Rabelinka,*, Erik S.G Stroesa, K.Paul Bouterb and Paul Morrisonc

aDepartment of Nephrology and Hypertension, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, Netherlands
bDepartment of Internal Medicine, Bosch Medicentrum, Utrecht, Netherlands
cKendle/U-Gene Clinical Pharmacology Unit, Utrecht, Netherlands

* Corresponding author. Tel: +31-30-250-7329; Fax: +31-30-254-3492; E-mail: t.rabelink@digd.azu.nl

Received 19 March 1998; accepted 22 May 1998


   1 Introduction
Top
 1 Introduction
2 Chronic renal failure:...
 3 Is endothelin a...
 4 Is ET-1 a...
 5 Pharmacology of the...
 6 Clinical countdown
 7 Conclusion
 References
 
The endothelin (ET) family comprises three 21-amino acid peptides: ET-1, ET-2 and ET-3. Endothelin-1 has been identified as the major cardiovascular isopeptide. Release of the active peptide ET-1 requires cleavage of a Trp21–Val22 bond in the carboxyterminal of the precursor molecule, big ET-1 [1]. This reaction is catalyzed by a membrane bound metalloprotease, endothelin converting enzyme (ECE-1) [1, 2]. An intracellularly located ECE (ECE-2) has been identified as well [3]. Endothelin release is increased transcriptionally when the endothelium is exposed to vasoconstrictor peptides, inflammatory cytokines and physical factors (e.g. angiotensin II, thrombin, TGF-β). Although the human kidney contains mRNA for all three isoforms of endothelin (ET), ET-1 appears to be the only peptide expressed at the protein level [4]. Expression of ET-1, its precursor, big ET-1, and the ECE in the non-diseased kidney is largely confined to the glomerular and vascular endothelium [4, 5]. However, when proteinuria is present, there is tubular expression of ET-1 as well [6]. ET-1 released by the renal vasculature or nephron segments mainly acts on cells in the immediate vicinity in an autocrine/paracrine fashion. ET-1 mediates its biological effects by interacting with two receptors, the ETA and ETB receptors, which have been cloned and well characterized. The ETA receptor is preferentially expressed in vascular smooth muscle cells and mediates the potent constrictor actions of ET-1 [7]. The ETB receptor is primarily expressed in endothelial cells and binds all three ET isoforms. When this receptor is activated, nitric oxide and prostacyclin are released, possibly as a feedback loop to the constrictor actions of ET-1. This is exemplified by recent observations where both administration of a selective ETB antagonist in animals as well as specific knock-out of the ETB receptor resulted in hypertension [8]The ETB receptor is also widely expressed in renal epithelium, where, in a paracrine fashion, it probably promotes sodium excretion and regeneration of damaged tubular epithelium [7, 9]. In some vascular beds the ETB receptor may also mediate constrictor actions at the level of the vascular smooth muscle cell [10]. However, in the human kidney, selective stimulation of the ETB receptor did not reduce renal blood flow [11]. In the kidney, ET-1 is the most potent vasoconstrictor known, acting both on the glomerular afferent and efferent arterioles [12–16]. Administration of exogenous ET-1 in animal models as well as in humans results in a profound fall in renal perfusion and GFR [12, 14–16]and sodium retention. These effects override the vasodilatory and natriuretic actions of the paracrine renal ET-system. Systemic increments as well as local renal activation of ET-1 may thus result in renal ischemia and promote the development of acute renal failure [17–20]. Using endothelin receptor blockers, a role for endothelin has been demonstrated in models of acute renal failure following ischemia, cyclosporin administration and radiocontrast nephrotoxicity [19–27]. These experimental data on models of acute renal failure hold the promise for the future application of endothelin receptor blockers in this area. Besides its constrictor effects, endothelin can stimulate mesangial proliferation and induce collagen and laminin synthesis [28–30]. Based on these observations, endothelin has also been implicated as a mediator of renal fibrosis [31–33]. Strong support for a pathogenetic role of endothelin in progressive renal disease was recently provided by studies on ET-1 transgenic mice. These mice have extensive glomerular sclerosis and renal interstitial fibrosis [34]. Such studies exemplify the potential role of ET-1 in the progression of renal disease. Therefore, if endothelin receptor blockers are going to be developed for renal disease, a likely indication will be chronic progressive renal failure. In this review, we will discuss the necessity for further drug therapy in this area, as chronic renal failure is emerging as a major form of end-organ damage in cardiovascular disease.


   2 Chronic renal failure: a cardiovascular complication?
Top
 1 Introduction
 2 Chronic renal failure:...
3 Is endothelin a...
 4 Is ET-1 a...
 5 Pharmacology of the...
 6 Clinical countdown
 7 Conclusion
 References
 
In Europe and the USA, the incidence and prevalence of end-stage renal disease is increasing dramatically. In the USA, more than a quarter of a million patients are being treated for end-stage renal disease (ESRD) [35]. The cost of treatment for ESRD in 1995 in the USA was 13.1 billion dollars. ESRD is also accompanied by an (unacceptably) increased morbidity and mortality [36–40]. This is underscored by the fact that the annual mortality rate from dialysis-dependent end-stage renal failure is 20% [35]. Projections suggest that the burden of illness from kidney disease will continue to rise until fundamental advances in the prevention and treatment of ESRD have been achieved. The increase in patients with ESRD is mainly caused by an increasing number of patients with diabetic nephropathy reaching end-stage renal failure, as well as patients with hypertensive nephrosclerosis or hypertensive atherosclerotic renal disease [41]. In the most recent surveys, diabetes and hypertension account for 40 and almost 30% of the ESRD population, respectively. These figures are even more alarming when one realizes that the World Health Organization (WHO) estimates that the diabetes population will double worldwide in the next 15 years, soaring to 450 million affected subjects. As such, end-stage renal disease is emerging more and more as a critical end organ in cardiovascular disease.


   3 Is endothelin a mediator of diabetic nephropathy?
Top
 1 Introduction
 2 Chronic renal failure:...
 3 Is endothelin a...
4 Is ET-1 a...
 5 Pharmacology of the...
 6 Clinical countdown
 7 Conclusion
 References
 
Many studies have now shown that patients with diabetes may have increased plasma levels of endothelin [42, 43]as well as increased urinary excretion of ET-1 when albuminuria is present [44, 45]. In fact, there appears to be a good correlation between these parameters and the severity of diabetic nephropathy [46]. Insulin has been identified as one possible stimulator of endothelin secretion in these patients [47, 48]. For example, elevated plasma endothelin levels have been reported in lean non-insulin-dependent diabetes mellitus patients during euglycemic hyperinsulinemic clamp [49]. However, factors other than insulin may also play a role in the activation of the ET-1 system in diabetes. Increased ET-1 expression has been demonstrated in glomeruli isolated from rats with streptozotozin-induced diabetes, which could be partially normalized by insulin administration [50]. Whether glucose itself is a stimulus of endothelin secretion under these conditions is still a matter of debate [51, 52]. Zoja et al. [53]and Remuzzi et al. [54]have put a very interesting alternative hypothesis forward to explain endothelin activation in the diabetic kidney. They found that ET-1 secretion by tubular cells could be stimulated by albumin and other high molecular weight proteins [53, 54]. This led them to suggest that secretion of ET-1 by the tubular epithelium into the renal interstitium could stimulate interstitial fibroblasts to proliferate and synthesize extracellular matrix proteins. This theory has gained further interest by recent observations that this stimulatory effect of albumin could be dependent upon binding to receptors for advanced glycation end products (RAGEs) in the tubuli [55]. Taken together, such data are suggestive of a role of endothelin in the progression of diabetic nephropathy. The recent introduction of ET receptor blockers may help to define this role. In this respect, it is of interest that, in the diabetic rat, chronic (24 weeks) ET receptor blockade reduced transcription of growth-related genes as well as mRNA levels for extracellular matrix proteins in glomeruli [56, 57].


   4 Is ET-1 a mediator of hypertensive renal disease?
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 1 Introduction
 2 Chronic renal failure:...
 3 Is endothelin a...
 4 Is ET-1 a...
5 Pharmacology of the...
 6 Clinical countdown
 7 Conclusion
 References
 
Because of its vasoconstrictor actions and effects on vascular hypertrophy, ET-1 has also been implicated in the pathogenesis and maintenance of hypertension. The exact role of endothelin in hypertension, however, remains to be established. Whilst in some experimental models of hypertension, such as DOCA salt hypertension and SHRSP (stroke-prone spontaneously hypertensive rats), vascular hypertrophy coincides with increased ET-1 expression and an antihypertrophic and blood pressure lowering effect of ET receptor blockade [58–62], there was no increased expression of ET-1 and no effect of ET receptor blockers in other models, such as the SHR and renal vascular hypertension models [59, 63]. Data in humans are still very scarce. Overexpression of ET-1 only occurs in small arteries of severe hypertensive patients [64]and could not be detected in normotensive subjects or mild hypertensive patients [64]. In normotensive subjects and in subjects with heart failure, ET receptor blockers do not appear to have important blood pressure lowering effects [65, 66]. However this may be different in hypertension. Indeed, a recent study reported that the mixed ET receptor antagonist, bosentan (see Table 1), could reduce blood pressure in mild hypertensives in a manner similar to that of an angiotensin-converting enzyme (ACE) inhibitor [67]. Unlike e.g. black hypertensives [68]or patients with malignant hypertension [64], these patients with mild hypertension do not have increased circulating ET-1 or enhanced tissue expression of ET-1, suggesting that the blood pressure lowering effects could even be stronger in the former groups. Interestingly, with respect to the kidney, ET receptor blockers may have a protective effect beyond blood pressure lowering. This is exemplified by studies of experimental hypertension where ET receptor blockade prevented histological injury in the kidney, although there was only a modest reduction in the hypertension [69–71]. This suggests a direct effect of ET receptor blockade on the fibrotic processes involved in hypertensive renal disease. This was also confirmed by a study of experimental malignant hypertension, where a mixed ETA/ETB blocker prevented the development of renal injury to a greater extent than hydralazine, despite a similar reduction of blood pressure by both drugs [72]


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  		Table 1 Compounds that are currently being developed to block the endothelin system

 

   5 Pharmacology of the endothelin system
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 1 Introduction
 2 Chronic renal failure:...
 3 Is endothelin a...
 4 Is ET-1 a...
 5 Pharmacology of the...
6 Clinical countdown
 7 Conclusion
 References
 
Over the last years, several orally available ET-receptor blockers have been developed with specific affinity for the ETA receptor, as well as with blocking effects for both the ETA and the ETB receptor (Table 1). In the setting of renal disease, the issue of whether ETA selective blockers are superior to mixed ETA/ETB antagonists is still unresolved. Clearly, the ETB receptor mediates important processes in renal physiology, such as sodium and water excretion, while it may also locally release vasodilator substances. Particularly in chronic renal disease, but also in e.g. heart failure, one would prefer not to interfere with these processes. On the other hand, it should be noted that, in animal studies, mixed antagonists are usually as effective as ETA-selective blockers in preventing the progression of renal disease (see below). A major problem for endothelin receptor blockers in the clinical arena is their toxicity. The endothelin receptor blockers that are now in clinical development frequently cause headaches and may be associated with liver toxicity [67]. Even more importantly, ET-1 is crucial for embryogenesis and ET receptor blockers, as well as any other pharmacological reduction in ET-1 activity, will therefore inevitably be teratogenic, which limits its application in women of child-bearing potential.

Another way to interfere with the endothelin system is by blocking the ECE. ECE is inhibited by the neutral endopeptidase inhibitor (NEP) phosphoramidon, but not by other NEP inhibitors or ACE inhibitors [73]. However, phoshoramidon is not a very potent and selective ECE inhibitor. Several experimental compounds that may be more selective for ECE are under investigation [8, 74, 75]. Although knowledge about the regulation of the ECE system in the kidney is still very limited, it is of interest that ECE may be a rate-limiting factor in the production of mature ET-1 (Yanagisawa, personal communication), while ECE has been found to be upregulated in disease states [76, 77]. The extent to which the intracellularly localized ECE contributes to the biological actions of ET-1, and whether or not this should be a pharmacological target, is also unknown.

The endothelin system has also shed new light on the neutral endopeptidase inhibitors. Systemic administration of NEP inhibitors does not consistently decrease blood pressure, despite the fact that it increases circulating levels of the natriuretic peptides and causes natriuresis [78]. In fact, local administration of the NEP inhibitor thiorpan in the forearm circulation even causes vasoconstriction [79]. A recent study demonstrated that this vasoconstriction could be abolished by ETA receptor blockade, indicating that NEP inhibition may offset its potential beneficial effects by reducing the catabolism of ET-1. This would suggest that dual ECE/NEP or ETA/NEP inhibitors may be particularly useful in the treatment of cardiovascular disease [80].


   6 Clinical countdown
Top
 1 Introduction
 2 Chronic renal failure:...
 3 Is endothelin a...
 4 Is ET-1 a...
 5 Pharmacology of the...
 6 Clinical countdown
7 Conclusion
 References
 
There is little doubt of the necessity for further improvement in the prevention and therapy of end-stage renal disease, and experimental data have provided us with a rationale for the possible role of ET receptor blockers, both in diabetic progressive renal disease as well as hypertensive renal disease. What can ET receptor blockers add to our current therapeutic strategies in this field?

6.1 Hemodynamic effects:

1. Blood pressure control is of paramount importance in controlling progression and possibly even the development of diabetic nephropathy as well as hypertensive nephropathy [81]. For example, in non-insulin-dependent diabetes patients, increases in both systolic and diastolic pressures using 24 h ambulatory blood pressure measurements (even in the upper range of traditionally accepted normal values) were associated with increased albuminuria [82]. The recent data with bosentan in hypertensives certainly look promising but need confirmation in renal patients with hypertension.
2. ET receptor blockers should also have an antiproteinuric effect. In patients with diabetes, microalbuminuria is an independent risk factor for progression of renal disease. Moreover, it is associated with a four–six-fold increase in cardiovascular mortality in these subjects [83]. In non-diabetic disease, macroalbuminuria is also a major risk factor for progression [84]. It is now generally assumed that this proteinuria does not only reflect renal damage, but may also contribute to further scarring of the kidney by causing protein overload and excessive tubular protein reabsorption [30–32, 85, 86]. Additionally, reduction of proteinuria is known to have a strong predictive value for renal outcome [87]. Of great interest are recent studies in experimental diabetes and NO-deficient hypertension where mixed and ETA-selective ET receptor blockade, respectively, reduced proteinuria [69, 88].

6.2 Interaction with the renin angiotensin system
Currently, inhibition of the renin angiotensin system in the kidney is the gold standard therapy for diabetic nephropathy [89]. More recent studies suggest that it is also effective in non-diabetic renal disease [90]. Therefore, the introduction of ET receptor blockers as a treatment for progressive renal disease, like in heart failure, has to be considered in the context of ACE inhibitor or AT-1 blocker therapy. Angiotensin II has now been identified as an important stimulator of endothelin synthesis in endothelial cells, vascular smooth muscle cells and mesangial cells [91–93]. Angiotensin may not only regulate local ET-1 levels by increasing transcription of prepro ET [94], but it may also enhance the activity of ECE [95]. From this perspective, it could be argued that endothelin is a mediator of the actions of angiotensin II. In support of this argument, ET receptor blockade was shown to attenuate both the hypertensive actions as well as the effects on vascular hypertrophy of chronic infusion with angiotensin II [96, 97]. This concept was recently confirmed in vivo in humans where captopril was shown to suppress plasma ET-1 levels both in basal as well as insulin-stimulated conditions [48]. ACE inhibitor therapy also reduced tissue endothelin expression in experimental nephritis [98]. The latter effect appeared to be independent of changes in blood pressure, but was accompanied by a reduction in proteinuria, further indicating that proteinuria could be a key mediator in ET activation in renal disease. Thus, data are accumulating now to show that ET-1 could be an effector mechanism of exogenously administered angiotensin II. Whether or not this also holds true for endogenous angiotensin II activation remains to be established. For example, in renal vascular hypertension, ET receptor blockade had no effect on blood pressure or vascular structure [99].

If the concept that part of the effects of angiotensin II are dependent upon stimulation of ET-1 is true, one may wonder whether or not we actually need ET receptor blockers and whether or not the effects of endothelin receptor blockade may add to those of ACE-inhibition. On the other hand, ACE inhibition or AT-1 receptor blockade may at best cause a partial reduction of ET-1, and more complete blockade of the effects of ET-1 may be obtained by combined therapy. This is of relevance as inflammatory cytokines, such as interleukin-1, tumor necrosis factor and TGF-β, which are known to promote renal fibrosis, can also stimulate renal ET-1 production [7], while ACE inhibitors cannot directly antagonize the effects of ET-1 [100]. Moreover, we recently demonstrated that selective ETA receptor blockade, both in the human resistance vasculature as well as in the hypertensive kidney, increases local nitric oxide activity [76, 101]. Such effects may also add to those induced by ACE-inhibition or AT-1 receptor blockade. There are also data that indicate that part of the ET receptor blocker actions in the kidney are independent of the renin angiotensin system. In the model of the remnant kidney, ETA receptor blockade caused a blood pressure reduction that was not altered by co-administration of an ACE-inhibitor [102]. However, the most exciting information in this respect was recently presented at a meeting in Kyoto, where it was shown by Webb et al. [8]that intravenous administration of an ET receptor blocker in patients with advanced renal failure caused a 10% reduction in blood pressure and a decrease in the filtration fraction similar to that seen with ACE inhibitors. Importantly, ACE inhibitor therapy in these patients was stopped only 24 h before administration of the ET receptor blocker, which implies that, with this degree of renal failure, the ACE inhibitor probably was not eliminated by this stage and the effects of ET receptor blockade could indeed add to those of an ACE inhibitor.


   7 Conclusion
Top
 1 Introduction
 2 Chronic renal failure:...
 3 Is endothelin a...
 4 Is ET-1 a...
 5 Pharmacology of the...
 6 Clinical countdown
 7 Conclusion
References
 
With the improved management of acute cardiovascular complications, end-stage renal disease is dramatically increasing as a complication of cardiovascular disease. This causes a huge social as well as economic burden on our society. Therefore, strategies that can improve the prevention of end-stage renal disease are urgently needed. Experimental data suggest that ET receptor blockade could be a novel therapeutic approach to end-stage renal failure. The protective effects of ET receptor blockers on vascular hypertrophy and renal injury appear to be partially independent of blood pressure lowering. This underscores the rationale for using them in the treatment of progressive renal disease. However, it also implies that ET receptor blockers probably have to be used in conjunction with other antihypertensive medication. As is also the case in heart failure, the interaction with ACE inhibitors and AT-1 blockers is of crucial importance in this respect. Fortunately, this has not discouraged pharmaceutical industries from entering this clinical area. Finally, although data are still very limited, the discovery of dual ECE/NEP and even ECE/NEP/ACE inhibitors may open exciting new avenues in therapy for renal end-organ damage.

Time for primary review 27 days.


   References
Top
 1 Introduction
 2 Chronic renal failure:...
 3 Is endothelin a...
 4 Is ET-1 a...
 5 Pharmacology of the...
 6 Clinical countdown
 7 Conclusion
 References
 

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B. Hocher and M. Paul
Transgenic animal models for the analysis of the renal endothelin system
Nephrol. Dial. Transplant., July 1, 2000; 15(7): 935 - 937.
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