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European Journal of Clinical Investigation (2006) 36 (Suppl.

3), 78 88

Role of endothelin and endothelin receptor antagonists


Blackwell Publishing Ltd

in renal disease

W. Neuhofer* and D. Pittrow


*University of Munich, Munich, Germany, University of Dresden, Dresden, Germany

Abstract Endothelin (ET)-1 is a potent vasoconstrictor peptide with pro-inflammatory, mitogenic,


and pro-fibrotic properties that is closely involved in both normal renal physiology and
pathology. ET-1 exerts a wide variety of biological effects, including constriction of cortical
and medullary vessels, mesangial cell contraction, stimulation of extracellular matrix
production, and inhibition of sodium and water reabsorption along the collecting duct, effects
that are primarily mediated in an autocrine/paracrine manner. Increasing evidence indicates
that the ET system is involved in an array of renal disorders. These comprise chronic
proteinuric states associated with progressive glomerular and tubulointerstitial fibrosis,
including diabetic and hypertensive nephropathy, glomerulonephritis and others. In addition,
ET-1 is causally linked to renal disorders characterized by increased renal vascular
resistance, including acute ischaemic renal failure, calcineurin inhibitor toxicity, endotoxaemia,
hepatorenal syndrome and others. Furthermore, derangement of the ET system may be
involved in conditions associated with inappropriate sodium and water retention; for
example, in congestive heart failure and hepatic cirrhosis. Both selective and non-selective
ET receptor antagonist have been developed and tested in animal models with promising
results. As key events in progressive renal injury like inflammation and fibrosis are mediated
via both ETA and ETB receptors, while constrictor effects are primarily transduced by ETA
receptors, dual ET receptor blockade may be superior over selective ETA antagonism. Several
compounds have been developed with remarkable effects in several models of acute and
progressive renal injury. Thus, clinical studies are required to assess whether these results
can be confirmed in humans, hopefully leading to novel and effective therapeutic options
with few side effects.
Keywords Acute renal failure, chronic kidney disease, endothelin system, glomerular injury,
tubulointerstitial injury.
Eur J Clin Invest 2006; 36 (Suppl. 3): 7888

Introduction pro-fibrotic, and pro-inflammatory properties, ET-1 has


been involved in several pathologies, including those
The discovery of ET-1 in the late 1980s by Yanagisawa et al. affecting the kidney.
[1] prompted extensive work on the role of ET-1 in both ET-1 is an important modulator of normal renal function
normal and pathological physiology. An abundant body of via its binding to abundant receptors in renal tissue and by
evidence has emerged since then, implicating ET-1 in both the ability of renal endothelial and epithelial cells not only
(reviewed in [2]). Particularly due to its vasoconstrictory, to respond to circulating ET-1 but also to synthesize and
release ET-1. In general, the effects of ET-1 in the kidney
are primarily mediated in an autocrine/paracrine fashion
Department of Physiology, University of Munich, Munich, and to a lesser extent to ET-1 derived from the systemic
Germany (W. Neuhofer); Department for Clinical Pharmacology, circulation. Thus, the local tissue concentrations may be
Medical Faculty, University of Dresden, Dresden, Germany several-fold higher than the levels measured in the systemic
(D. Pittrow).
circulation. In conditions characterized by progressive
Correspondence to: PD Dr Wolfgang Neuhofer, Department glomerular and tubulointerstitial injury (i.e. hypertensive
of Physiology, Pettenkoferstrasse 12, 80336 Munich, Germany. nephropathy, diabetic nephropathy, glomerulonephritis)
Tel.: +49 89 218075203; fax: +49 89 218075512; locally produced and released ET appears to mediate the
e-mail: Wolfgang.Neuhofer@med.uni-muenchen.de majority of the detrimental effects in an autocrine and para-
Received 7 July 2005; accepted 31 May 2006 crine manner. The biological effects of ET-1 are mediated

2006 The Authors


Journal compilation 2006 Blackwell Publishing Ltd
Endothelin in the kidney 79

by at least two G-protein-coupled receptors, namely ETA will be summarized. Finally, the role of ET-1 in acute renal
and ETB, which, in pathophysiology, cooperatively induce injury will be addressed and results obtained in experimental
a variety of intracellular events, thereby causing vaso- models will be discussed.
constriction, proliferation, inflammation and extracellular
matrix production [3 5]. Furthermore, ET-1 reduces the
expression of matrix-metalloproteinase-1 and zymographic
activity [4], thereby additionally contributing to fibrosis. Role of the endothelin system in normal renal
Up-regulation of ET-1 and its cognate receptors has been physiology
convincingly demonstrated within the respective lesions,
suggesting that circulating ET-1 may play only a minor role. The ET system modulates RBF, GFR, reabsorption of
A contribution of systemically produced ET-1 however, sodium and water, and acid-base balance. Both ETA and
cannot be completely excluded, because exogenous admini- ETB receptors are expressed in renal vessels, in mesangial
stration of ET-1 is able to cause a significant decrease in cells and in tubular epithelial cells. ETA receptors are
renal blood flow (RBF) and glomerular filtration rate (GFR) expressed in large quantities in cortical vessels, in pericytes
at concentrations that do not affect systemic blood pressure of descending vasa recta, within glomeruli, and interstitial
[6]. Several factors peculiar to acute and chronic kidney cells from the inner and outer medulla [16,17]. ETB recep-
disease (CKD) have the ability to stimulate the expression tors are most abundant in cells from the inner medullary
of ET-1 in renal cells, including proteinuria, transforming collecting duct (IMCD) and in glomeruli [16,17].
growth factor (TGF)-, angiotensin II (Ang II), hyper- Most studies have shown that infusion of pressor doses
glycaemia, hypoxia, calcineurin inhibitors, and many others. of ET-1 into the renal artery results in a decreased urinary
ET-1 mediated activation of nuclear factor kappaB sodium excretion which occurs secondary to reductions in
(NF-B) is a critical event in the initiation and progression both GFR and RBF [18]. However, ET-1 not only regulates
of inflammation and fibrosis, because NF-B regulates the water and sodium excretion indirectly by modulating these
transcription of several genes involved in progressive renal parameters, but also directly. In the renal medulla, activa-
damage. In agreement, NF-B abundance increases most tion of ETB receptors abates sodium and water absorption
prominently in those structures that are most intensely along the medullary collecting duct and increases medullary
affected during the disease process [7]. In experimental models, blood flow [19,20], both causing natriuresis and diuresis.
NF-B activation could be prevented by ET-1 antagonism Several lines of evidence suggest that ETB receptor-
with bosentan, thus leading to impaired expression of cell mediated inhibition of epithelial sodium channel (ENaC)
adhesion molecules, monocyte chemoattractant protein-1, in the IMCD is responsible for reduced sodium absorption
and to a decrease in vasculopathy and fibrosis [79]. in this nephron segment in response to ET-1 [21,22].
Progressive renal diseases associated with chronic pro- Although ETA receptors are expressed on pericytes of
teinuria are characterized by glomerulosclerosis and descending vasa recta and exogenous ET-1 causes intense
tubulointerstitial fibrosis. Fibrosis is caused by fibroblast focal constrictions of isolated vasa recta [23], ET-1 increases
proliferation and excessive production of extracellular medullary blood flow in vivo. This phenomenon most likely
matrix proteins. The ET system is closely involved in the results from ETB-mediated release of nitric oxide from adja-
process of renal remodelling, as demonstrated by over- cent tubular segments [19], which may block the constrictor
expression of ET-1 in mice. These animals develop interstitial effects of ET-1. Furthermore, ET-1 decreases osmotic water
fibrosis, glomerulosclerosis, and other renal abnormalities permeability by six-fold in vasopressin-stimulated IMCD
[10,11], thus likely contributing to progression of CKD. cells [24]. Thus, the mechanism of diuresis and natriuresis
The notion that ET plays an active role in CKD is further is linked to reduced sodium reabsorption along collecting
supported by the observation that the extent of renal ducts, elevated medullary blood flow and to an endothelin-
damage directly correlates with renal ET-1 levels in rats [12]. mediated inhibition of vasopressin action in the IMCD,
In addition, acute renal failure (ARF) has been recognized which are mediated by ETB receptors. By these mech-
as one of the first pathophysiological settings in which ET- anisms, the ET system participates in the regulation of blood
1 has been causally implicated, in particular due to the pressure [19,21,25]. In a normal, healthy kidney, ETB
observation that the renal vasculature is strongly sensitive blockade appears to result in sodium and water retention.
to ET-mediated vasoconstriction [6,13]. Furthermore, However, in a diseased kidney, expression of ET receptors
increased ET-1 gene expression occurs in response to a is modulated, with elevated expression of ETB at those sites
variety of noxious stimuli, including ischaemiareperfusion that are affected by the pathological process. The ET
injury, administration of radiocontrast media, myoglobinuria, system, through ETB, also plays a role in renal acid-base
and others [1315], thereby possibly aggravating the initial regulation. Several lines of evidence suggest that ETB is
insult by ET-1 mediated ischaemia and inflammation. involved in stimulation of proximal tubular sodium/proton
In the following, a brief summary will be provided on exchanger isoform 3 (NHE3) after acid challenge, thus
the role of ET-1 in normal renal physiology. Thereafter, the leading to increased proton secretion [26].
impact of the ET system in progression of CKD characterized Apart from these important roles in normal physiology,
by glomerular and tubulointerstitial fibrosis (i.e. diabetic the ET system is closely involved in several conditions lead-
nephropathy, hypertensive nephropathy, glomerulonephritis) ing to CKD and ARF. Endothelin receptor antagonists
will be highlighted and results obtained from animal models (ERA) have demonstrated remarkable effects in both

2006 The Authors


Journal compilation 2006 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 36 (Suppl. 3), 7888
80 W. Neuhofer and D. Pittrow

settings in animal models. In the following, the role of the


ET system in selected renal disorders will be reviewed and
the therapeutic potential of ERA will be addressed.

Role of endothelin in the pathophysiology


of chronic kidney disease

Progression to end-stage renal failure is the final common


pathway of many chronic proteinuric diseases including
hypertensive and diabetic nephropathy, and glomerulone-
phritis [27,28]. Glomerular barrier dysfunction with
elevated filtration of proteins has been identified as a major
risk factor for CKD progression in patients with chronic
immunological or non-immunological nephropathies
[2729]. During the progression of CKD, those nephrons
that have been initially spared by the disease process activate
compensatory mechanisms to preserve GFR; for example,
an increase in single nephron GFR by elevation in glomer-
ular capillary pressure, while proximal tubular epithelial
cells undergo hypertrophy to deal with elevated solute load
[27]. In these nephrons, hyperfiltration occurs with con-
comitant structural glomerular and tubular injury in a
self-perpetuating cycle [27,28]. During the last decade it
has become increasingly clear that protein accumulation in
the proximal tubular lumen, as a consequence of glomerular
permeability dysfunction, is directly involved in tubular cell
injury (Fig. 1) [28,30,31]. A causal role for proteinuria in Figure 1 Putatitive pathogenetic model of endothelin-mediated
the development of progressive CKD is further supported tubulointerstitial injury in progressive renal disorders.
by the observation that the severity of urinary protein excre-
tion correlates with the extent of renal damage and that
manoeuvres reducing proteinuria ameliorate renal injury to adjacent tubules, which further aggravates tubulointer-
[28]. Those proteins that are filtered accumulate in the prox- stitial injury. In agreement, in several animal studies on
imal tubular lumen and are actively reabsorbed by proximal renal mass reduction, a model for functional nephron loss,
tubular epithelial cells. Excessive protein reabsorption, the ET system has been implicated in the disease process.
however, results in intracellular protein overload and is Orisio et al. demonstrated a time-dependent increase in
associated with increased production of vasoactive and renal ET-1 gene expression and urinary ET-1 immuno-
pro-inflammatory mediators, in particular ET-1, which reactivity, which correlated with proteinuria and progression
is primarily released into the basolateral compartment of renal damage [12]. In addition, Bruzzi et al. showed that
where it promotes interstitial inflammation, fibroblast pro- ET-1 expression was particularly abundant at those sites
liferation and deposition of extracellular matrix proteins, with structural lesions. Two weeks after renal mass reduc-
thus ultimately leading to tubulointerstitial fibrosis (Fig. 1) tion, ET-1 mRNA expression was confined to tubular cells;
[29,3133]. after 4 weeks, however, when glomerulosclerosis became
Up to now, a large body of evidence has emerged indi- apparent, ET-1 transcripts were further detected within the
cating that ET-1 is substantially involved in the process of affected glomeruli [36]. A direct genetic approach to eluci-
progressive renal injury due to proteinuria [15,29,32,34]. date the role of ET in progressive renal injury has been
Plasma ET-1 levels in patients with CKD are significantly independently provided by Hocher et al. and Shindo et al.
higher than in healthy subjects and urinary excretion of [10,11]. The authors demonstrated that mice over-expressing
ET-1 exceeds that of control subjects by four- to five-fold [35]. ET-1 time-dependently developed glomerulosclerosis,
The increase in urinary ET-1 excretion most likely results interstitial fibrosis and renal cysts [10,11]. The occurrence
from intrarenal production and tubular secretion, rather than of pathologic alterations was further accompanied by a
clearance from the systemic circulation. Cultured proximal decline in GFR. While no effect on systemic blood pressure
tubular cells exposed to excess proteins show a dose- was detected in the study by Hocher et al. [11], those mice
dependent production and release of ET-1, which is released engineered by Shindo et al. developed salt-dependent
primarily into the basolateral compartment [33]. In addi- hypertension and proteinuria at 12 months of age [10].
tion, tubule-derived ET-1 and ET-1 produced within In view of the pro-inflammatory and pro-fibrotic effects
glomeruli may lead to constriction of peritubular capillaries of ET-1, several lines of evidence suggest that ET-1 may, at
and descending vasa recta with subsequent hypoxic damage least partially, mediate the detrimental effects of TGF- in

2006 The Authors


Journal compilation 2006 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 36 (Suppl. 3), 7888
Endothelin in the kidney 81

human pathologies. Both ET-1 and TGF- are regulated in tension-induced end organ damage, in which ERA reduced
parallel and TGF- is one of the most potent modulators proteinuria, expression of adhesion molecules, tubu-
of ET-1 gene expression and ET-1 release in mesangial lointerstitial inflammation and vascular hypertrophy, and
cells, tubular epithelial cells, vascular smooth muscle cells, improved renal function and survival.
endothelial cells and others [37 40]. In agreement, in vivo Mller et al. showed in Ang II-induced hypertension in
administration of TGF- in mice resulted in elevated ET-1 mice that bosentan treatment strongly reduced structural
expression within the kidney, which was accompanied by renal lesions and proteinuria, in addition to significantly
tubulointerstitial fibrosis and vasoconstriction [37]. These enhanced survival [8]. Furthermore, Ang II-induced acti-
alterations were most pronounced at the corticomedullary vation of NF-B, expression of adhesion molecules in
junction and in medullary vasa recta bundles, and fibrosis glomeruli and tubular epithelial cells, and macrophage
was correlated to focal tissue hypoxia [37]. In vitro studies infiltration were suppressed by bosentan, which occurred
on collecting duct cells demonstrated that blocking endo- independent of blood pressure [8]. Boffa and Chatziantoniou
genous TGF- by neutralizing antibodies or antisense- used a rat model of NG-nitro-L-arginine methyl ester
oligodeoxynucleotides attenuated auto- and paracrine ET-1 (L-NAME)-induced hypertension in transgenic mice
release [40]. In addition, in human fibroblasts, ET-1 and expressing the luciferase gene under control of the promoter
TGF- showed synergistic effects on cell cycle progression from the collagen I gene as a measure for collagen type I gene
and collagen production that were much more pronounced activation [44,46]. These animals developed hypertension
in combination than with either of the substances alone and showed extracellular matrix deposition in glomeruli
[41]. and afferent arterioles, which was accompanied by elevated
Besides TGF-, the ET system may also cooperate with luciferase activity within these structures and increased
the renin-angiotensin system in progression of renal fibrosis. urinary ET-1 excretion. Co-administration of bosentan with
Based on the observation that exogenous angiotensin II L-NAME, however, prevented the structural alterations and
(Ang II) increases ET-1 expression in the kidney, it has been reduced collagen type I promoter activity [44,46]. Interest-
suggested that ET-1 may mediate the pathogenetic effects ingly, these beneficial effects occurred without alterations
of Ang II [42]. Indeed, Ang II stimulates ET-1 secretion in blood pressure. Subsequently, Boffa et al. showed in the
in rat mesangial cells and tubular epithelial cells [43] and same model that application of bosentan after renal fibrosis
several studies demonstrated that ET-1 antagonists might had already developed, resulted in regression of renal sclerotic
prevent Ang II-induced structural lesions. Moreaux et al. lesions, and reduced mortality [47].
showed that blocking the ET system prevents vascular
medial hypertrophy induced by angiotensin II infusion [42].
Both ET-1 and Ang II dose-dependently stimulate matrix Endothelin receptor antagonists in diabetes
protein synthesis and mitogenesis in mesangial cells, while
these effects are abolished by ET-1 receptor blockade. In Diabetic nephropathy is the major cause of end-stage renal
agreement, Ang II-induced activation of the collagen type disease and patients with diabetes have elevated circulating
I gene in renal cortex was blunted by bosentan [44], ET-1 levels [48,49]. Over-expression of ET-1 and ET recep-
indicating that the pro-fibrotic actions of Ang II are at least tors has been demonstrated in diabetic nephropathy in
partially mediated by ET. Furthermore, Gomez-Garre glomeruli and tubular epithelial cells [50] and ERA have
et al. found in a model of chronic proteinuria-induced been effective in several experimental models on diabetic
nephropathy, that angiotensin converting enzyme inhibition nephropathy. Thus, ET-1 apparently contributes significantly
and bosentan treatment synergistically prevented NF-B to kidney damage in diabetes.
activation and structural renal lesions [7]. Chen et al. demonstrated in streptozotozin-induced
In Table 1, the role of the ET system in major human diabetes in rats, that expression of ET-1, ETA and ETB
pathologies associated with progressive renal fibrosis is receptors was elevated, along with increased abundance of
summarized and the most impressive effects of ERA under fibronectin and collagen 2(IV), and glomerular basement
these conditions are outlined. It shows a comprehensive thickening due to extracellular matrix deposition [51].
overview of studies evaluating ERA in chronic and acute These alterations were prevented by bosentan, indicating
renal disorders. that structural lesions in diabetes may be at least partially
caused by activation of the ET system [51]. Accordingly,
Cosenzi et al. showed in the same model, that bosentan
Endothelin receptor antagonists in hypertension prevented the increase in urinary protein excretion and
intrarenal expression of immunoreactive collagen, fibronectin
Development of sclerotic lesions is one the most common and TGF- without reducing blood pressure [52]. Nakamura
renal complications in hypertension, which develop along et al. demonstrated, that an experimental ETA receptor
with increased circulating ET-1 levels. The underlying antagonist, given to diabetic rats at the disease induction
pathophysiology entails structural changes by abnormal (i.e. streptozotozin treatment), prevented the development
accumulation of extracellular matrix (mainly collagen type of renal injury and preserved renal function [53]. Interest-
I) in renal resistance vessels, glomeruli and interstitium ingly, using the same experimental model, Benigni et al.
[45]. The concept that ET-1 is a major pathogenic mediator showed that non-selective ET antagonism was reno-
in this process is supported by several models on hyper- protective, even when administrated while the animals were

2006 The Authors


Journal compilation 2006 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 36 (Suppl. 3), 7888
82 W. Neuhofer and D. Pittrow

Table 1 Overview of effects of endothelin receptor antagonists (ERA) in models of acute and chronic renal failure

Model Species ERA specificity Outcome Reference

Ischaemic ARF R ETA/ ETB Preservation RBF, GFR (compared to AT1 receptor blockade) [70]
R ETA/ ETB, ETA Preservation of GFR, amelioration of increase in FENa, FEK [76,77]
R ETA/ ETB Preservation of renal function and proximal tubular structure, [71]
also effective when given in the post-ischaemic period
R ETA Prevention of proximal tubular necrosis (S3 segment) [75]
amelioration of increase in FENa
R ETA Preservation of GFR, amelioration of increase in FENa, [73,74]
also some effect when given in the post-ischaemic period
C ETA/ ETB, ETA Preservation of GFR, amelioration of increase in FENa [72]
Cold ischaemia prior R ETA/ ETB Prevention of tubular cell necrosis and cell detachment, [84]
to transplantation increases creatinine clearance
Preretrieval warm ischaemia R ETA/ ETB, ETA Prevention of decline in GFR, ETA/ETB antagonism effective [81,82]
prior to transplantation after 2 month
Cyclosporine A toxicity H ETA/ ETB Prevention of decline in RPF [87]
R ETA/ ETB Improvement in cortical blood flow and renal function [95]
R ETA/ ETB Improvement in renal function, no effect on structural alterations [96]
Acute liver and renal failure R ETA/ ETB Prevention of renal failure after onset of liver failure [91]
(hepatorenal syndrome)
LPS-induced renal failure R ETA/ ETB Prevention of deterioration of renal function [94]
in cirrhosis
Renal mass reduction R ETA Attenuation of glomerular injury, preservation of renal function [97]
R ETA/ ETB Preservation of renal function, reduced mortality, reduction [98]
of proteinuria and blood pressure increase
R ETA/ ETB, ETA Amelioration of glomerulosclerosis [99]
Diabetes R ETA/ ETB Prevention of proteinuria, reduction of increase in [52]
(streptozotozin-induced) renal immunoreactive collagen I, fibronectin, TGF-
R ETA/ETB Reduction of proteinuria, normalizatiom of RBF, reduction [50]
of ET-1 expression, effective when given after onset of
proteinuria
R ETA/ ETB Prevention of increased fibronectin and collagen alpha2(IV) [51]
expression, increased mesangial matrix deposition and
GBM thickening
R ETA/ ETB, ETA Normalization of glomerular matrix protein expression [100]
R ETA Amelioration of proteinuria, reduction of glomerular [53]
expression of matrix proteins and growth factors
Unilateral ureteral obstruction R ETA/ ETB Prevention of reduction in RBF, reduced apoptosis [101]
Passive Heyman nephritis R ETA Amelioration of hypertension, significant effects on structural [60]
and renal function only when combined with ACEI
Immune complex nephritis R ETA/ETB Amelioration of proteinuria, functional and structural [59]
improvement, decrease in urinary ET-1 excretion
Lupus nephritis M ETA Prevention of structural and functional deterioration [102]
PAN nephritis R ETA Decreased expression of some glomerular matrix proteins [103]
Hypertension R ETA/ETB Normalization of collagen I gene expression, regression renal [47]
(L-NAME-induced) vascular fibrosis, improved survival
R ETA/ ETB Reduction of collagen I gene expression and sclerotic lesions [104]
R ETA/ ETB Reduction of proteinuria and glomerulosclerosis [105]
Hypertension R ETA/ ETB Amelioration of vascular hypertrophy [106]
(DOCA-hypertensive)
R ETA Reduction of blood pressure, no reduction of renal injury [107]
and renal ET-1 expression
R ETB Decrease in sodium and water excretion [108]
R ETB Exacerbation of hypertension [109]
Hypertension R ETA Amelioration of vascular hypertrophy [42]
(Angiotensin II infusion)
Hypertension R ETA Prevention of renal damage, reduction in mortality [110]
(UNX stroke-prone
spontaneously hypertensive)
Hypertension (SHRSP) R ETA Prolonged survival, at high dosage haemorrhages in basal ganglia [111]

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Journal compilation 2006 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 36 (Suppl. 3), 7888
Endothelin in the kidney 83

Table 1 Continued

Model Species ERA specificity Outcome Reference

Hypertension R ETA Reduced proteinuria, glomerular damage, blood pressure [112]


(Dahl salt-sensitive rats)
Hypertension (SHR) R ETA/ ETB Normalization of renal function, no effect on blood pressure [113]
Hypertension (2K1C) R ETA Exacerbation of fibrosis [114]
Hypertension R ETA/ ETB Reduced proteinuria, improved renal function, reduction [8]
(transgenic approach) of adhesion molecule expression, tubulointerstitial
inflammation, and vascular hypertrophy
Inappropriate sodium R ETA/ ETB Reduction of renal vascular resistance, improvement of [115]
and water retention sodium and water excretion
(congestive heart failure)
C ETA No improvement in renal sodium excretion, further activation [116]
of the renin-angiotensin system
Polycystic kidney disease R ETA/ ETB, ETA Cyst growth by ETA blockade, reduction of RBF by ETA [117]
(Han-Sprague-Dawley rats) blockade
Primary hyperaldosteronism H ETA/ ETB, ETA Decrease in aldosterone levels by combined ETA/ ETB blockade, [118]
but not by selective ETA antagonism

Abbreviations: 2K1C, two kidney-one clip renovascular hypertension; ACEI, angiotensin converting enzyme inhibitor; ARF, acute renal
failure; AT1, angiotensin II type 1 receptor; ERA, endothelin receptor antagonist; DOCA, deoxycorticosterone acetate; ET, endothelin;
GFR, glomerular filtration rate; GBM, glomerular basement membrane; FENa, fractional excretion of sodium; FEK, fractional excretion
of potassium; PAN, puromycin aminonucleoside; RBF, renal blood flow; RPF, renal plasma flow; SHR, spontaneously hypertensive rats;
SHRSP, salt-loaded stroke-prone spontaneously hypertensive rats; UNX, uninephrectomy.

already proteinuric [50]. Thus, in addition to angiotensin GN. Lehrke et al. demonstrated that patients with IgA
converting enzyme inhibitors, ERA may offer an additional nephropathy exhibited increased abundance of ET-1 and
therapeutic option in the treatment of diabetic nephropathy, ETB receptors, which were most pronounced in glomeruli
in particular in those cases with advanced disease. and proximal tubules. Moreover, ET-1 and ETB expression
within these structures correlated with the severity of
proteinuria [58]. These results indicate that elevated ET-1
Endothelin receptor antagonists in signalling through ETB receptors may be causally involved
glomerulonephritis in the progression of chronic glomerular diseases, thereby
contributing to glomerular barrier dysfunction and extra-
The major morphological feature in most forms of progres- cellular matrix expansion within glomeruli. Filtered pro-
sive glomerulopathies is the proliferation of mesangial cells teins would be reabsorbed by proximal tubular cells, which,
and the expansion of extracellular matrix. The pathogenetic in turn release ET-1 abluminally, thus initiating tubulointer-
role of ET-1 in this context is underscored by the observa- stitial injury. Consistently, in a rat model of proliferative
tion that ET-1 is mitogenic for mesangial cells and induces immune complex nephritis, bosentan ameliorated both
matrix protein synthesis [54]. Elevated intrarenal produc- proteinuria and glomerular lesions [59]. In another model
tion of ET-1 has been demonstrated in animal models of on passive Heymann nephritis, however, selective ETA
glomerulonephritis, including experimental membranous blockade was only effective when combined with ACE inhi-
glomerulopathy (passive Heymann nephritis) [55], NZB/ bition [60], suggesting that dual ERA may be potentially
WF1 mice (model of immune-complex nephritis) [56], more efficacious than selective ET antagonists. In summary,
puromycin aminonucleoside nephrosis (model of human the use of ERA in glomerulonephritis may be useful in
minimal change disease) [57], and in patients with IgA inhibiting both excessive fibrogenetic activity and counter-
nephropathy [58]. Nakamura et al. showed in NZW/WF1 acting inflammation, in particular in those patients who do
mice, that renal ET-1 mRNA abundance was increased not respond adequately to established therapies such as the
10-fold with a concomitant rise in ETA and ETB receptors inhibition of the renin-angiotensin system.
[56]. Steroid treatment in turn prevented these alterations
as well as structural lesions [56]. Further, in puromycin
aminonucleoside-induced nephrosis, glomerular ET-1 and
ETB expression was elevated two- to three-fold compared Role of endothelin in the pathophysiology of acute
to controls and declined during remission of nephrosis. renal failure
In contrast, glomerular ETA receptor mRNA levels were
not affected [57]. The observations from animal models are Although potentially reversible, mortality rates in ARF are
in good agreement with data derived from humans with high, in particular in patients with post-operative ARF [61].

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Journal compilation 2006 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 36 (Suppl. 3), 7888
84 W. Neuhofer and D. Pittrow

ARF may develop in response to a variety of noxious insults ET-1 blockade may be more efficient in improving the early
including ischaemia, radiocontrast media, myoglobinuria, course of post-ischaemic renal injury than Ang II inhibition
calcineurin inhibitors and other toxins. Ischaemia, however, and blockade of ET-1 might be even effective in prophylaxis
remains the major cause of ARF [62]. In the clinical set- of ischaemic ARF. Several additional studies demonstrated
ting, ischaemic ARF occurs frequently following cardiovascular a positive effect of ERA after ischaemic ARF, as assessed
surgery, post-transplantation or severe trauma, haemor- by preservation of renal haemodynamics and GFR, by
rhage, hypotension (e.g. cardiac arrest), sepsis and/or vol- reduced sodium excretion and perpetuation of tubular
ume depletion [62]. The pathophysiological mechanisms structure [7175]. The major drawback of most reports,
underlying ischaemic ARF are complex and still incom- however, is the fact, that ERAs were administrated prior to
pletely understood [62]. The major target in ischaemic ARF and during the ischaemic period. Later application during
is the outer medulla, which, because of its role in urine con- the reflow period was ineffective in most cases [73 77].
centration, is a chronically hypoxic environment [63,64]. It Importantly, the dual ET receptor antagonist tezosentan
has been known for some time that there is much less flow has recently been shown to prevent the rise in serum cre-
to the medullary than to the cortical capillaries in the post- atinine as well as tubular necrosis, and to improve inulin
ischaemic kidney, resulting in an imbalance between oxygen clearance even when administrated after ischaemia [71],
and nutrient supply and tubular work (oxygen demand) in suggesting that dual ERA may be potentially useful in the
the renal medulla [63,64]. Consequently, injury of medullary clinical setting.
cells results in enhanced expression of cell adhesion mole-
cules, release of vasoconstrictors (i.e. ET-1), pro-inflammatory
cytokines with subsequent leukocyte activation, thereby Endothelin receptor antagonists in renal
leading to sustained intrarenal vasoconstriction and con- transplantation
gestion of medullary vessels, which further aggravates outer
medullary damage. Pre-retrieval warm ischaemic injury predisposes to delayed
The observation that exogenous ET-1, applied via the graft function and is a strong predictor of long-term graft
renal artery, is able to decrease RBF and GFR to create con- loss, thus representing an established non-immunological
ditions that can lead to ARF, suggests a major contribution risk factor for an adverse outcome [78,79]. Utilization of
of ET-1 in several forms of ARF. Indeed, the renal circulation organs subjected to ischaemia /reperfusion injury could
appears to be exceptionally responsive to ET-1 mediated expand the donor pool, which is, however, complicated by
vasoconstriction [6]. Furthermore, ET-1 mRNA expression, the fact that about 30% of cadaveric renal allografts, but
ET-1 content and its affinity for ET receptors are elevated almost never living-donor kidneys, develop post-ischaemic
in ARF and increased ET-1 levels persist for days after acute renal-transplant failure [80]. As ET-1 is an important
resolution of the initial injury [65]. In addition, recent data mediator of ARF associated with renal transplantation, ERA
indicate that inflammation plays a major role in the patho- may influence the post-transplant outcome beneficially
physiology of ischaemic ARF [66]. Importantly, ET-1 [81,82].
stimulates expression of adhesion molecules on endothelial Warm ischaemia, cold ischaemia and preservation
cells and production of cytokines and oxygen species by damage induce an increase in renal ET-1 expression in the
monocytes and neutrophils [67,68]. At least in macro- reperfusion phase, contributing both to the deterioration of
phages, the ETB receptor is responsible for signalling to renal function and to tubular necrosis [81,83]. Interestingly,
NF-B and cytokine production, underscoring again the bosentan prevented tubular cell necrosis, cell detachment
importance of ETB in pathophysiology [69]. Thus, there and increased renal function in a model of renal trans-
may be another rationale for endothelin receptor antago- plantation with pre-retrieval warm ischaemia [84]. Further-
nism in ARF in view of the pro-inflammatory properties of more, Inman et al. demonstrated that chronic application
ET-1. of a non-selective ERA mitigated the decline in GFR
two months after pre-retrieval warm ischaemia [81].
Cyclosporine A-induced nephrotoxicity is a major problem
Endothelin receptor antagonists in ischaemic acute in cyclosporine A therapy and is mainly due to ET-mediated
renal failure vasoconstriction and vascular structural lesions [85,86].
Interestingly, co-administration of cyclosporine A with
Several experimental studies on ischaemic ARF have been bosentan in humans increased renal plasma flow compared
performed investigating the effect of selective and non- to placebo and thus counteracted cyclosporine A-induced
selective ERA in this setting. In a recent study of post- vasoconstriction [87]. ERA may also be useful in transplant
ischaemic ARF in rats, Jerkic et al. compared the effect of renal arteriosclerosis, which is characterized by concentric
bosentan to that of losartan (Ang II type 1 [AT1] receptor neointimal thickening and which is one of the major causes
antagonist) [70]. In the ARF group treated with bosentan, of chronic rejection in human kidney transplantation [88].
RBF was increased by 129% compared to 35% losartan- Support for an involvement of the ET system comes from
treated rats. Furthermore, GFR was markedly higher in the observation that renal ET-1 production and excretion
bosentan-treated rats than in all other groups on the first is increased in patients on long-term treatment with
and second day after ischaemia, and tubular cell injury was cyclosporine A [89]. Thus, in view of the constrictory and
attenuated by bosentan but not by losartan [70]. Thus, dual proliferative activity of ET-1, the ET system may be involved

2006 The Authors


Journal compilation 2006 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 36 (Suppl. 3), 7888
Endothelin in the kidney 85

in the development of transplant renal arterosclerosis, and


ERA may be useful for ameliorating cyclosporine A-induced
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2006 The Authors


Journal compilation 2006 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 36 (Suppl. 3), 7888

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