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3), 78 88
in renal disease
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
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
Table 1 Overview of effects of endothelin receptor antagonists (ERA) in models of acute and chronic renal failure
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]
Table 1 Continued
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].
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
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