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Endothelin and Tubulointerstitial Renal Disease

Albert C.M. Ong, MD, PhD,* Karoline von Websky, DVM,† and Berthold Hocher, MD, PhD†

Summary: All components of the endothelin (ET) system are present in renal tubular cells. In this review, we
summarize current knowledge about ET and the most common tubular diseases: acute kidney injury (AKI) and
polycystic kidney disease. AKI originally was called acute tubular necrosis, pointing to the most prominent
morphologic findings. Similarly, cysts in polycystic kidney disease, and especially in autosomal-dominant
polycystic kidney disease, are of tubular origin. Preclinical studies have indicated that the ET system and
particularly ETA receptors are involved in the pathogenesis of ischemia-reperfusion injury, although these
findings have not been translated to clinical studies. The ET system also has been implicated in radiocontrast-
dye–induced AKI, however, ET-receptor blockade in a large human study was not successful. The ET system
is activated in sepsis models of AKI; the effectiveness of ET blocking agents in preclinical studies is variable
depending on the model and the ET-receptor antagonist used. Numerous studies have shown that the ET
system plays an important role in the complex pathophysiology associated with cyst formation and disease
progression in polycystic kidney disease. However, results from selective targeting of ET-receptor subtypes in
animal models of polycystic kidney disease have proved disappointing and do not support clinical trials. These
studies have shown that a critical balance between ETA and ETB receptor action is necessary to maintain
structure and function in the cystic kidney. In summary, ETs have been implicated in the pathogenesis of
several renal tubulointerstitial diseases, however, experimental animal findings have not yet led to use of ET
blockers in human beings.
Semin Nephrol 35:197-207 C 2015 Elsevier Inc. All rights reserved.
Keywords: Endothelin, acute kidney injury, polycystic kidney disease, ADPKD, ET-1, ETA, ETB

cardiac procedures are increasing steadily.3 Evidence

A
cute kidney injury (AKI) is a clinical syndrome
that is characterized by a rapid decrease in is accumulating that the renal endothelin (ET) system is
glomerular filtration rate (GFR). The decrease involved in the development and maintenance of AKI.
in renal function is accompanied by retention and
accumulation of waste products such as urea and
creatinine, and very often is characterized by decreased ENDOTHELIN IN ISCHEMIA-REPERFUSION INJURY
urine output, increased plasma potassium and phos- OF THE KIDNEY
phate concentrations, metabolic acidosis, and changes
in body fluid balance. It can result from several Shortly after the discovery of ET as a very potent
disorders that affect the kidney acutely and many vasoconstrictor, it was suggested that this peptide plays
different pathways are involved in the complex patho- an important role in the pathogenesis of AKI.4 Infusion
genesis. The cause of AKI differs somewhat depending experiments with rat kidneys showed that exogenous ET
on the population (community-acquired), country, and reduces renal blood flow and GFR, resembling hypoper-
site of onset (hospital-acquired or before hospitaliza- fusion and hypofiltration observed in postischemic kid-
tion). Renal ischemia-reperfusion injury (IRI) repre- neys.5,6 At the same time, it was shown that endogenous
sents a very common cause of AKI1: sepsis-induced ET was increased in renal tissues in a rat model of
AKI is the most common form of AKI observed in ischemic acute renal failure.7 Wilhelm et al8 showed that
critically ill patients and accounts for at least 50% of renal ET-1 concentrations are increased during the initial
cases in the intensive care unit.2 Contrast-induced 24 hours after reperfusion in experimental ischemic AKI.
nephropathy (CIN) has become the third leading cause Firth and Ratcliffe9 reported long-lasting increases in renal
for hospital-acquired AKI because interventional ET-1 messenger RNA (mRNA) expression after ischemia,
suggesting a role for ET in maintaining postischemic
* glomerular dysfunction. These and ensuing studies clearly
Kidney Genetics Group, Academic Nephrology Unit, Department
of Infection and Immunity, University of Sheffield Medical School, showed that increased renal ET-1 mRNA expression and
Sheffield, UK. ET-1 formation occurs with renal IRI.10

Institute for Nutritional Science, University of Potsdam, Potsdam, Subsequently, several experiments investigating the
Germany. effects of selective and nonselective ET-receptor block-
Financial support and conflict of interest statements: none. ade in the setting of renal IRI were published. Although
Address reprint requests to Berthold Hocher, MD, PhD, Institute for several investigators were able to show beneficial effects
Nutritional Science, University of Potsdam, 14558 Nuthetal,
Potsdam, Germany. E-mail: hocher@uni-potsdam.de on renal function and morphology in animal models of
0270-9295/ - see front matter IRI,11–15 there also were conflicting data showing no
& 2015 Elsevier Inc. All rights reserved. functional protection with ET-receptor blockade in
http://dx.doi.org/10.1016/j.semnephrol.2015.03.004 postischemic renal injury.16–18 Neuhofer and Pittrow19

Seminars in Nephrology, Vol 35, No 2, March 2015, pp 197–207 197


198 A.C.M. Ong, K. von Websky, and B. Hocher

suggested differences in the time point of drug treatment coronary/vascular interventions. CIN is the third most
as a possible explanation (ie, before, during, or after the common cause of new-onset renal injury in hospitalized
ischemic period). However, Wilhelm et al20 showed that patients and is associated with increased morbidity and
treatment with the nonselective ETA/ETB-receptor antag- mortality.25 Contrast media might exert direct tubular cell
onist tezosentan both before and after the ischemic toxicity mediated by free radicals, oxidative stress,
period successfully decreased serum creatinine level, cytokine-induced inflammation, and apoptosis.25,26 Renal
increased GFR, and maintained renal architecture in medullary hypoxia caused by a selective reduction in
kidneys after ischemia. Recently, Zager et al18 inves- blood flow to the outer medulla may be an important
tigated the effects of ETA- or ETB-specific antagonists in contributory factor to the development of CIN27; when
a mouse model of IRI both before and after injury. Over oxygenation is impaired, medullary hypoxic injury with
the experimental period of 2 weeks after unilateral necrosis of the tubules occurs.28 Endothelin may be
ischemic injury, intrarenal ET-1 production increased involved in several of these pathogenic processes. In
as well as the expression of ETA, but not ETB. Although animal experiments, intravenous radiocontrast infusion
ETA blockade provided protective effects on the kidney, increases plasma and urinary ET-1 levels.29,30 Contrast
ETB blockade had no such effects. The investigators media can directly damage endothelial cells in renal
concluded that interaction between ET-1 and ETA might vessels,31 which may explain the observed increase in
have an important role in AKI leading to chronic kidney ET-1 levels. Administration of ET-receptor antagonists
disease. These results suggested that intervention with prevented renal vasoconstriction32,33 as well as improved
ETA-receptor antagonists could be a therapeutic option functional and structural markers32–36 in animal models
for slowing or preventing the progression from posti- of radiocontrast nephrotoxicity (Table 2).
schemic AKI to chronic kidney disease (CKD).18 Results from studies of the human renal ET system
Comparable results were found in a different model of in patients with CIN are scarce. In 1997, Clark et al37
IRI in mice lacking ET-1 in vascular endothelial cells. showed in 19 patients undergoing arteriography that
One day after IRI induced by bilateral clamping of the circulating ET-1 levels increased after large-volume,
renal pedicles, these animals showed significantly less but not small-volume, contrast exposure. An even
vascular and tubular injury than the control group. In smaller study (n ¼ 6) investigated the role of ET in
control wild-type mice, vascular and tubular injury were CIN in patients with chronic renal failure. Application
associated with up-regulated ET-1 and ETA expression.21 of contrast media increased urinary ET excretion
This experiment also underlined the importance of (corrected by creatinine concentration) in patients with
endothelial cells in the microvasculature in IRI. Endo- pre-existing impaired renal function but not in patients
thelial dysfunction is a major contributor to ischemic with normal renal function.38 A few other studies have
renal damage and is characterized by an imbalance investigated ET-1 plasma levels before and after
between the release of ET-1 and nitric oxide (NO).22 application of contrast media and found either no
Damage to vascular endothelial cells during reperfusion differences39 or an increase in plasma ET levels after
may lead to the release of ET from injured endothelial contrast administration.40,41 Ulas et al42 showed an
cells, followed by sustained intrarenal vasoconstriction increase in urinary and plasma ET-1 concentrations in
and thus hypoxic injury of the adjacent tubules.8,23 78 patients but provided no information on renal
In diabetes, these events may be even more pronounced function. Until now, only two larger prospective
because insulin resistance results in widespread endothelial clinical studies of the renal ET system before and
dysfunction with increased levels of ET-1 and decreases in after exposure to contrast media in patients with renal
NO through disruption of NO synthase. This further disease have been conducted. The first study showed
impairs renal vascular autoregulation.22 In rats treated with that ET-receptor antagonism and intravenous hydra-
streptozotocin, IRI led to a more severe renal phenotype tion exacerbated radiocontrast nephrotoxicity com-
than in nondiabetic animals. With the use of selective ETA pared with hydration alone in patients with chronic
blockers, a partial improvement of kidney function in renal insufficiency undergoing cardiac angiography.43
diabetic rats that underwent IRI was observed.22 RNA However, the dose of the ETA/ETB antagonist was
interference with a short hairpin RNA for ETA partially not established in phase 2 studies in advance of this
silenced gene expression and led to improved renal phase 3 trial. A large observational study found a
function and structure in IRI injury in rats24 (Table 1). decrease in urinary ET concentration as well as the
urinary ET-1/creatinine ratio after application of con-
trast medium in patients with diabetes or renal impair-
ENDOTHELIN IN CONTRAST DYE–INDUCED ACUTE ment undergoing coronary angiography.3 The urinary
ET-1 concentration and the urinary ET-1/creatinine
KIDNEY INJURY
ratio after contrast application were higher in patients
Acute kidney injury frequently occurs after exposure to who had a persistent decrease in GFR of at least
iodinated contrast media for cardiac angiography and 25% after 90 days of follow-up evaluation. No major
ET and tubulointerstitial renal disease 199

Table 1. ET-Receptor Blockers in Animal Models of Ischemia-Reperfusion Injury of the Kidney


Reference Antagonist/Knockout
Model Outcome Model Species
11
ETA (BQ-123) Preserved renal function Bilateral clamping of Rats
Prevention of proximal tubular necrosis renal artery and
vein
12
ETA (BQ-123) Treatment before renal arterial clamping: beneficial effects on Bilateral renal artery Rats
renal function clamp for 45 min
ETA (BQ-123) Treatment only during the reperfusion period: no effects on Bilateral renal artery
renal function clamp for 45 min
13
ETA (BQ-123) In rats with severe AKI: improved survival rate Uninephrectomized þ Rats
Markedly improved tubular function 45-min renal artery
clamp
ETA (BQ-123) Moderately increased GFR 30-min renal artery
þ
In rats with moderate AKI: increased Na reabsorption clamp
No effect on renal hemodynamics
15
ETA/ETB (SB 209670) In rats with severe ARF when infused on the day after Uninephrectomized þ Rats
ischemia: markedly increased survival rate 45-min renal artery
clamp
Increased tubular reabsorption of Naþ Uninephrectomized þ
ETA/ETB (SB 209670) Slow and gradual increase in GFR 30-min renal artery
clamp
In rats with moderate ARF when infused 24 hours after
ischemia: reversed impairment in Naþ reabsorption without
increasing GFR or renal blood flow
16
ETA (PD 156707) Both antagonists: attenuated cellular infiltration and matrix Uninephrectomized þ Rats
accumulation 45-min renal artery
clamp
ETA/ETB (SB 209670) Reduced apoptosis
17
ETA (SB 234551) No effects on function Uninephrectomized þ Rats
Increases in urinary protein and albumin 45-min renal artery
ETA/ETB (SB 209670) Decrease in GFR and creatinine clearance clamp
18
ETA (Atrasentan) Decreased tubule/microvascular injury, total preservation of 30-min renal artery CD-1
renal mass clamp mice
ETB (BQ 788) ETB blockade had no protective effects

Abbreviation: ARF, acute renal failure.

long-term complications of CIN (need for dialysis, ENDOTHELIN IN SEPSIS-INDUCED ACUTE KIDNEY
rehospitalization, or death) were associated with renal INJURY
ET levels in this study.
The findings from these two larger studies in human Increased ET-1 plasma levels in septic patients are
beings, and especially the negative effects of ET- associated with the severity of the illness46 and may be
receptor blockade, are contradictory to promising involved in renal complications during sepsis.47 The
results in CIN from animal studies. This discrepancy ET-1 level in kidney tissue is increased in a time-
could be partially attributable to a higher incidence of dependent manner after lipopolysaccharide (LPS)
hypotension in the treated population in the clinical administration to rats.48,49 Increased ET levels in
trial. Further reasons are discussed extensively by Wang plasma and tissues are believed to be a consequence
et al.43 Another point that has to be taken into account of an up-regulation of ET-1 synthesis in vascular
is that the existing animal models for CIN are probably endothelial cells of various organs as well as endothe-
not of adequate translational value.3 Therefore, we need lial injury.48 Over the past few years of research on
better CIN animal models closer to human pathophysi- AKI, a new concept for the pathogenesis of renal
ology (models should consider risk factors leading to failure in early sepsis has emerged.2,50 It now is being
CIN such as diabetes or heart failure). Clinical develop- questioned if global renal ischemia resulting from
ment requires proper dose finding in phase 2 trials systemic hypotension is the main reason for the loss
before initiating an outcome study to avoid unwanted of GFR, a traditionally held dogma.51 It has been
effects on blood pressure (Table 3).44,45 shown in animal models52,53 and in human studies54,55
200 A.C.M. Ong, K. von Websky, and B. Hocher

Table 2. ET-Receptor Blockers in Animal Models of CIN


Reference Antagonist Outcome Model Species
32
ETA/ETB Fully reversed decrease of renal Sodium iothalamate, Rats
(CP170687) perfusion indomethacin
33
ETA/ETB (SB Decrease in renal vascular resistance Tri-iodinated ionic contrast Dogs
209670) Decrease of renal blood flow media, indomethacin
34
ETA (SB-209670) With both antagonists: GFR less Lopamidol, indomethacin, Rats
reduced L-NAME
Urinary flow reduced
ETA/ETB (BMS- Renal blood flow without change
182874) Less morphologic necrosis
Less morphologic necrosis
35
ETA (A-127722) Reduction of protein excretion and Diatrizoate, indomethacin, Rats
plasma creatinine L-NAME
36
ETA (BQ123) No effect on cortical flow, Iopromide Rats
outer medullary blood flow, and
ETB (BQ788) outer medullary oxygen tension
Less reduction of
outer medullary oxygen tension

Abbreviation: L-NAME, L-NG-nitroarginine methyl ester.

that sepsis-induced AKI may occur despite an increase also was observed with dual ETA/ETB blockade in
or no decrease in total renal blood flow (RBF). Changes neonatal piglets during endotoxemia.58 In contrast,
in the relation of afferent-efferent arteriolar resistance, neither selective nor combined ETA and ETB blockade
which are triggered by intrarenal hemodynamic factors, improved GFR in a rat model of endotoxin-induced
including ET-1, might modulate GFR. The role of ET- acute kidney dysfunction. Selective ETB antagonism
1 in renal complications in sepsis has been investigated caused renal vasoconstriction and reduced RBF in this
in animal experiments using ET-receptor antagonists. experimental setting. According to the investigators,
ET-receptor blockade is useful in preventing albumi- this showed that ETB might be involved in the
nuria during endotoxin shock in conscious, chronically preservation of renal blood flow via renal vasodila-
catheterized rats.56 Mitaka et al57 showed that non- tion.59 In this experiment, no change in medullary
selective ET-receptor blockade improved LPS-induced circulation was observed with ETA blockade, which
decreases in urine volume, RBF, creatinine clearance, is in contrast to the findings in endotoxemic pigs,
and urine osmolality in dogs. Improved renal function suggesting that ET reduces renal medullary perfusion

Table 3. Human Studies of CIN


Refer- Outcome After Radiocontrast
ence Cohort Exposure Intervention N
37
Diabetes mellitus and/or renal Increased ET plasma levels Angiography with
insufficiency iopamidol or
No change in serum creatinine diatrizoate meglumine 8
concentration
38
Patients with chronic In patients with renal impairment: Coronary and aortic angiography 6 versus
renal failure significantly and CT 6 controls
higher urinary ET excretion
corrected by creatinine
concentration
43
Patients with chronic renal In the ETA/ETB blocker group: Coronary angiography 77 versus
insufficiency with ETA/ETB increase in serum creatinine 81 placebo
blocker (SB 290670) with higher incidence of
radiocontrast nephrotoxicity
3
Patients with diabetes or renal Significant decrease of urinary Coronary angiography 38 with CIN
impairment ET concentration using iobitridol versus 255
controls

Abbreviation: CT, computed tomography.


ET and tubulointerstitial renal disease 201

owing to activation of ETA.53 A possible explanation Therefore, further research is needed to better under-
may be that medullary microvascular flow was not stand the role of the ET system in sepsis-induced AKI
reduced by LPS in the first mentioned study.59 Fen- (an overview of the preclinical studies is shown
hammer et al60 previously showed in a similar model in Table 4).
that treatment with tezosentan, a dual ETA/ETB antag-
onist, improved renal artery blood flow and renal
POLYCYSTIC KIDNEY DISEASE: BACKGROUND
cortical microcirculation in endotoxemia, but had no
effect on urine production. Therefore, the investigators Autosomal-dominant polycystic kidney disease
hypothesized that selective ETA antagonism would (ADPKD) is the most common genetic kidney disease
improve diuresis by preserving ETB function. A further in human beings with an estimated prevalence of 1:400
experiment in endotoxemic pigs did not confirm this and 1:1,000. It is the fourth most common cause of
because treatment with an ETA antagonist had no end-stage renal disease (ESRD), which occurs in 50%
significant effects on diuresis or creatinine clearance. of affected individuals before the age of 60 years.61
However, ETA antagonism attenuated endotoxemia- Almost all cases of ADPKD are caused by germline
induced microcirculatory impairment and ischemia in mutations in PKD1 or PKD2. The ADPKD proteins
the renal medulla. These findings question the advan- polycystin-1 (460 kDa) and polycystin-2 (110 kDa)
tages of a selective ETA antagonism compared with play critical roles in maintaining normal tubular struc-
combined ETA/ETB antagonism. Because LPS induces ture and function through the regulation of multiple
expression of both renal receptors,48 dual ET-receptor signaling pathways involving Ca2þ, mechanistic target
blockade may be promising in preventing renal of rapamycin (mTOR), and cyclic adenosine mono-
dysfunction in sepsis. However, the individual func- phosphate homeostasis.62,63
tional contributions of ET and its receptors in sepsis- Clear genotype-phenotype correlations have been
induced AKI need to be investigated further. Most reported in ADPKD.64 Nonetheless, it is well known
likely, they are important components of the patho- that there is marked intrafamilial phenotypic variability
genesis of sepsis-induced AKI, but their exact role in of ESRD onset in many PKD1 or PKD2 pedigrees.65
the complex glomerular and periglomerular changes in Conversely, there is concordance for ESRD between
hemodynamics and microcirculatory blood flow in the identical twins compared with their siblings.66 These
kidney is not clear.50 Discrepancies and contradictory studies confirm the likely importance of nonallelic
results in the aforementioned studies are obvious genetic factors (other genes, epigenetic modification)
and could relate to differences in the animal or gene-environment interactions in determining indi-
models of sepsis. Varying observation periods, diverse vidual phenotype.
pharmacologic substances, and, most importantly, spe- The pathophysiology of ADPKD is complex and
cies differences in the distribution of ET receptors includes changes in cell proliferation, apoptosis, fluid
in the kidney, might have functional implications. secretion, extracellular matrix formation, apoptosis,

Table 4. ET-Receptor Blockers in Animal Models of Sepsis-Induced Acute Kidney Injury


Reference Antagonist Outcome Model Species
53
ETA (TBC 3711) Reduced renal oxygen extraction and cortical Escherichia coli Pigs
levels of lactate endotoxin
No effects on cortical blood flow infusion
56
ETA (FR 139317) Both blockers: attenuated plasma volume and LPS Rats
ETA/ETB (Bosentan) albumin escape
57
ETA/ETB (TAK-044) Prevention of metabolic acidosis and hypoxemia LPS Dogs
Improved decreases in urine volume, renal blood
flow, creatinine clearance, and urine osmolality
58
ETA/ETB (tezosentan) Increased renal blood flow Endotoxin Pigs
Increased GFR
Decreased renal vascular resistance
59
ETA (BQ-123) Neither selective nor combined ETA- and ETB- LPS Rats
receptor blockade improved GFR
ETB (BQ-788) Marked reductions in renal blood flow
60
ETA/ETB (tezosentan) Increase in renal microcirculation and renal blood LPS Pigs
flow
Decrease in plasma creatinine
202 A.C.M. Ong, K. von Websky, and B. Hocher

angiogenesis, defective planar cell polarity, and cilia- investigating the influence of an SNP ETA (C/T poly-
mediated mechanosensation.62,67 The molecules morphism in exon 8) on disease progression in 193
involved in these processes could play rate-limiting ADPKD patients (87 males, 106 females), females with
steps in renal disease progression. Cysts commonly the CC genotype reached ESRD at a significantly later
occur in other organs and especially in the liver and age than CT heterozygotes (CC, 57.4 ⫾ 8.1 y; CT, 53.0
pancreas; major noncystic manifestations include ⫾ 9.1 y; and TT, 54.5 ⫾ 6.4 y).70 This SNP also was
hypertension (70%), left ventricular hypertrophy, associated with a lower pulse pressure and thus could be
aortic aneurysms, and cardiac valvular abnormal- protective in ADPKD patients.70 The same group also
ities,68 indicating that ADPKD is more than a kidney examined the influence of three SNPs in ET-1 (K198N,
disease. 3A/4A, and T-1370G) on progression to ESRD in 205
ADPKD patients.71 Of interest, carriers of the 4A allele
in combination with the 198N allele (4A/4A, 3A/4A þ
THE ROLE OF ENDOTHELINS 198KN,NN) had a significantly lower age of ESRD
ET-1 has been reported to exert multiple effects on onset (47.1 ⫾ 8.7 y), 6 years younger than the carriers
different aspects of renal physiology. Apart from of other genotypes.71 The deleterious effect of the
circulating ET-1, there is good evidence that many combination of 4A and 198N alleles of SNPs of ET-1
renal cell types, including tubular cells, synthesize and could be owing to a higher processing rate of preproET
bind ET-1.69 As discussed earlier, two major ET- into ET-1 in carriers of the 198N allele, leading to the
receptor subtypes, ETA and ETB, have been shown to higher ET-1 plasma levels.71 These studies suggest that
mediate ET-1 action in the kidney, but often with activation of the systemic ET-1 system in human
opposing effects. The potential role for endothelins as ADPKD could participate in disease progression, pos-
modifying factors in ADPKD disease progression have sibly by increasing systemic blood pressure and/or
been studied by several groups, are discussed later, and reducing RBF.
are summarized in Tables 5 and 6.

PLASMA OR CYST ET-1 LEVELS IN HUMAN ADPKD


SINGLE-NUCLEOTIDE POLYMORPHISMS OF
ET-1 AND ETA IN HUMAN ADPKD DISEASE Many renal cell types can synthesize and bind ET-1,
indicating its potential as an autocrine or paracrine
PROGRESSION
factor.69 In one study, concentrations of immunoreactive
Single-nucleotide polymorphisms (SNPs) of ET-1 and ET-1, cyclic adenosine monophosphate, and epidermal
ETA genes have been shown to have a modest effect on growth factor were found to be increased in human
the age of ESRD onset in ADPKD. In one study ADPKD cyst fluid.72 Another study reported that patients

Table 5. Preclinical Studies Linking the ET System With Polycystic Kidney Disease
Reference Antagonist Outcome Model Species
82
Develop renal cysts but not hypertension Blood pressure– hET-1
Renal cysts apparent prior to independent model of transgenic
glomerulosclerosis, interstitial fibrosis, and ET-1–induced renal mice
loss of GFR at 14 months pathology
Renal cysts apparent by 3 months
81
Salt-sensitive hypertension - mET-1
transgenic
mice
80
ETA (LU 135252) Tubular proliferation Cyst growth ADPKD Han:Sprague-
Dawley rats
ETA/ETB (LU 224332) Additional blockade of the ETB-receptor
attenuated these effects
86
ETB (A-192621) Accelerated cystic kidney disease ADPKD Pkd2 (WS25/-)
mice
ETA (ABT-627) Abolished effects of ETB blockade when given
simultaneously
83
ETB (BQ-3020) Hypoxia-induced tubular ET-1 synthesis In vitro primary cultured Human kidney
Stimulated endogenous ET-1 synthesis with cell system cells
BQ-3020

Abbreviations: hET-1, human ET-1; mET-1, mouse ET-1.


ET and tubulointerstitial renal disease 203

Table 6. Human Studies Linking the Endothelin System to ADPKD


Reference Analyzed Tissue Outcome N
72
Human ADPKD kidneys ET-1 present in human ADPKD cyst fluid 10
76
Human ADPKD kidneys Increased ETA expression in ADPKD kidneys 12
78
Human ADPKD kidneys Increased ETA gene expression in ADPKD tissue 12
77
Human ADPKD kidneys Increased ETA gene expression in kidney tissue 5

with ADPKD (hypertensive and normotensive) had diseases.82 Overexpression of ET-1 in these mice was
increased plasma levels of ET-1 in comparison with not associated with systemic hypertension, although
patients with essential hypertension or healthy subjects.73 salt-dependent hypertension could be induced in older
These studies suggested that both circulating and local ET- mice.81 The mechanism of cyst formation in these
1 systems are activated abnormally in human ADPKD. models mice was not clarified, although intrarenal
ischemia and tubular occlusion were proposed as
potential explanations.81
ET-1 AND ET-RECEPTOR EXPRESSION IN PKD
Increased levels of ET-1 have been reported in cystic
kidneys from experimental models and human disease, ET-1 AND TUBULAR CELL PROLIFERATION
although there are notable differences in the expression of
ET-1 was shown to be a potent mitogen in vitro for
ET-receptor subtypes. In the congenital polycystic kidney
normal human renal tubular cells and interstitial
(cpk) mouse model of PKD, renal ET-1 mRNA levels
fibroblasts; in addition, it can stimulate collagen I gene
were 3.2-fold greater than controls at 1 week, and 10-fold
expression in fibroblasts.83,84 Tubular ET-1 synthesis
greater at 3 weeks when cystic disease was at its height.74
has been documented in experiments from different
Similarly, renal ETA and ETB mRNA levels increased
species.69 Tubular cell proliferation is an early feature
4.2- and 6.3-fold over control kidneys, respectively.74 In
of precystic tubules in human ADPKD and many
the Han:SPRD rat model of PKD, significantly increased
rodent PKD models.85 A role for ETB in mediating
tissue levels of ET-1 were found in cystic kidneys, but
the mitogenic effect of ET-1 has been shown in human
ETA and ETB density were reported to be decreased
proximal tubular cells as part of a hypoxia-inducible,
markedly.75 In contrast, a study in human ADPKD cystic
forward-feedback, autocrine loop involved in renal
kidneys reported that ETA mRNA levels were 5- to 10-
tubular regeneration.83
fold higher than non-ADPKD controls, whereas ETB
mRNA was unchanged.76 In addition, neo-expression of
ETA receptors was detected overlying cyst epithelia,
SELECTIVE ETA OR ETB BLOCKADE IN PKD RODENT
glomeruli, and medium-sized arteries, regions where
MODELS
immunoreactive ET-1 also was present.76 The increase in
total kidney ETA mRNA levels in human ADPKD was To date, there have only been two studies using
confirmed in two subsequent studies using microarray selective ETA or ETB antagonists to delay cystic
platforms.77,78 disease progression in rodent PKD models.80,86 How-
Activation of the renal ET system in ADPKD could ever, there was a notable difference in the ET-receptor
result from stimulation by changes in the circulating subtype responsible for disease progression between
and local renin-angiotensin-aldosterone system owing the two models.
to cyst enlargement,79 resulting in focal ischemia and Chronic administration of an ETA-selective antago-
tissue hypoxia, both of which are strong stimuli for nist (LU135252 or darusentan) for 4 months led to
ET-1 synthesis.80 more severe cystic disease in the Han:SPRD rat. This
was associated with an increase in tubular cell pro-
liferation. The deleterious effect of ETA blockade was
ET-1 AND CYST INITIATION IN TRANSGENIC MICE
partially reduced by a nonselective ET-receptor antag-
Overexpression of ET-1 (human or mouse) in trans- onist (LU224332), presumably by blocking unopposed
genic mice is sufficient to trigger cyst initiation.81,82 ETB.80 Alternatively, ETA blockade indirectly could
ET-1 transgenic mice developed multiple cortical result in tubular cell proliferation through ischemia-
kidney cysts at as early as 3 months of age in addition induced hypoxia inducible factor–dependent tubular
to interstitial fibrosis and glomerulosclerosis, thus ET-1 synthesis and an ETB-mediated positive feedback
providing direct evidence that ET-1 alone can contrib- loop.83 The finding that ETA blockade induces tubular
ute to the initiation and progression of cystic kidney cell proliferation is different from that reported in other
204 A.C.M. Ong, K. von Websky, and B. Hocher

models of CKD or prostate cancer87,88 and appears


characteristic of PKD.
In a second study, Pkd2WS25/- mice were treated
from 5 to 16 weeks of age with the highly selective,
orally active, receptor antagonists atrasentan (or ABT-
627, ETA) or A-192621 (ETB), singly or in combina-
tion.86 Selective ETA blockade also resulted in a
significant increase in tubular cell proliferation in this
model but, unlike the previous study, did not alter the
overall cystic phenotype. Conversely, selective ETB
blockade led to accelerated cystic kidney disease
(including interstitial inflammation and fibrosis) with-
out altering tubular cell proliferation. The deleterious
effects of ETB blockade were mediated through
unopposed ETA action because these changes were
normalized by combined ETA and ETB blockade. In Figure 1. Pathophysiological pathways activated by ET in the
addition, ETB blockade resulted in a decrease in urine cystic ADPKD kidney. Cysts arise owing to germline PKD1 or
PKD2 mutations. Compression of the renal vasculature leads to
volume, reduced urinary sodium excretion, increased ischemia, hypoxia, and activation of the renin-angiotensin system,
urine osmolality, and renal cyclic adenosine mono- which in turn could activate ET-1 synthesis. ET-1 may stimulate
phosphate concentrations, features that suggest an cyst growth and interstitial fibrosis further through ETA and ETB
receptors via vasopressin-dependent and vasopressin-indepen-
enhancement of vasopressin action. It is likely, how- dent pathways.
ever, that vasopressin-independent pathways also are
involved.86 patients.92,93 Nonetheless, ETA blockade in the
These results could be explained by recent studies in Pkd2WS25/- model did not alter cystic disease severity
segment-specific knockout mice that have shown a despite the increase in ETB-mediated tubular cell
physiological role for local ET-1 acting via ETB in proliferation.86 This observation implies that an
regulating sodium and water excretion by kidney increase in cell proliferation alone does not stimulate
collecting ducts.89 ETB activation inhibits vasopressin cyst growth, presumably owing to a compensatory
action, thereby promoting diuresis and natriuresis.90 increase in apoptosis. Nonetheless, this could represent
ETB blockade therefore would potentiate vasopressin a potential longer-term safety signal for renal cancer.
action in cysts derived from the collecting duct and Selective ETB blockade apparently is deleterious and
thus stimulate cyst expansion.86 A primary role for should not be used in ADPKD.86
vasopressin in ADPKD disease progression likely is Numerous studies have shown that the ET system
based on the efficacy of vasopressin V2-receptor plays important roles in the complex pathophysiology
antagonists in suppressing cyst growth in rodent associated with cyst formation and disease progression
models of Autosomal recessive polycystic kidney in ADPKD. However, results from selective targeting
(ARPKD), ADPKD, and nephronophthisis, and in of both ET-receptor subtypes in animal models of PKD
human beings.67,91 have proved disappointing and do not support further
extension into clinical trials. These studies, however,
CLINICAL IMPLICATIONS have shown that a critical balance between ETA and
ETB action is necessary to maintain kidney structure
Figure 1 summarizes the potential pathogenic mecha- and function in the cystic kidney, especially through
nisms by which ET-1 could promote cyst growth in regulating the action of vasopressin. These results
ADPKD. In rodent PKD models, the balance between confirm that ET-1 and its receptors act as major
ETA and ETB signaling appears to be critical for modifying genes for ADPKD. Future challenges will
maintaining kidney structure and function. ETB acti- be to translate these findings to alter disease severity or
vation may suppress vasopressin action and increase predict prognosis in human beings.
vasodilation, tubular proliferation, and salt and ET-1
excretion in PKD, whereas ETA activation may
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