Physiology and pathology of endothelin-1 in renal mesangium
Andrey Sorokin1 and
Donald E. Kohan2
1Division of Nephrology, Medical College of
Wisconsin, Milwaukee, Wisconsin 53226; and 2Division
of Nephrology, University of Utah Health Sciences Center and Salt Lake
Veterans Affairs Medical Center, Salt Lake City, Utah 84132
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ABSTRACT
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Mesangial cells (MCs) play a central role in the physiology and
pathophysiology of endothelin-1 (ET-1) in the kidney. MCs release ET-1 in
response to a variety of factors, many of which are elevated in glomerular
injury. MCs also express ET receptors, activation of which leads to a complex
signaling cascade with resultant stimulation of MC hypertrophy, proliferation,
contraction, and extracellular matrix accumulation. MC ET-1 interacts with
other important regulatory factors, including arachidonate metabolites, nitric
oxide, and angiotensin II. Excessive stimulation of ET-1 production by, and
activity in, MC is likely of pathogenic importance in glomerular damage in the
setting of diabetes, hypertension, and glomerulonephritis. The recent
introduction of ET antagonists, and possibly ET-converting enzyme inhibitors,
into the clinical arena establishes the potential for new therapies for those
diseases characterized by increased MC ET-1 actions. This review will examine
our present understanding of how ET-1 is involved in mesangial function in
health and disease. In addition, we will discuss the status of clinical trials
using ET antagonists, which have only been conducted in nonrenal disease, as a
background for advocating their use in diseases characterized by excessive
MC-derived ET-1.
mesangial cell; cell signaling; receptor; pathophysiology
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REGULATION OF ENDOTHELIN-1 GENE EXPRESSION IN MESANGIAL CELLS
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WHILE THERE ARE THREE MEMBERS of the endothelin (ET) family
(ET-1, ET-2, and ET-3), ET-1 is the major renal isoform produced by and acting
on the mesangial cell (MC). ET-1 mRNA encodes a 212-amino acid prepropeptide
that is cleaved to 38-amino acid big ET-1, which, in turn, is converted by
ET-converting enzymes (ECEs) to mature 21-amino acid ET-1
(116). There are seven ECE
isoforms and three ECE genes: ECE-1a, -1b, -1c, -1d, -2a, -2b, and -3. ECE-1
and ECE-2 prefer big ET-1, whereas ECE-3 prefers ET-3
(50). The combination of a
short ET-1 mRNA half-life (
15 min)
(44) and limited intracellular
storage of ET-1 results in a close parallel between mRNA levels and peptide
secretion. Thus the release of active ET-1 peptide must be controlled via
1) regulation of gene transcription; 2) mRNA stabilization;
and/or 3) regulation of ECE activity.
Present data primarily implicate transcriptional control of ET-1 synthesis.
ET-1 mRNA stability is unchanged by thrombin or cytokines
(25,
65), and limited data are
available on the regulation of ECE expression or activity
(21). Numerous stimuli
modulate MC ET-1 gene transcription, including vasoactive substances, growth
factors, cytokines, G protein-coupled receptor agonists, and oxygen radicals
(Table 1). The cooperation of
tissue-specific transcription factors conveys a degree of tissue-selective
ET-1 mRNA transcription and ensures that ET-1 is not inappropriately activated
(115). This cooperation is
made possible by the presence of multiple regulatory elements in the ET-1
promoter, including binding sites for activator protein-1, GATA-2,
CAAT-binding nuclear factor-1 (NF-1), and cell-specific transcription factors
upstream of classic CAAT and TATAA boxes
(93). Importantly, these
regulatory elements operate in different cell types, promoting cell-specific
regulation of ET-1 mRNA synthesis [e.g., endothelium-specific transcription
factors Vezf1/DB1 (1) and
cardiac-specific GATA-4
(72)].
Regulation of ET-1 production has been extensively investigated in MCs. The
5'-flanking region of the ET-1 gene encompasses positive regulatory
elements (e.g., engaged by thrombin), whereas negative modulation is exerted
by the distal 5' portion
(25). Upregulation of
prepro-ET-1 expression requires p38 MAPK and PKC
(Fig. 1). Thrombin and
cytokines (TNF and IL-1) synergistically increase ET-1 expression in MCs, an
effect requiring activation of p38 MAPK and PKC, whereas ERK, JNK/SAPK, or
intracellular Ca2+ release is uninvolved
(25). The events upstream of
p38 MAPK activation likely involve TGF-
-activated kinase 1-binding
protein-1, TNF receptor-associated factor 2, and several MEKKs
(Fig. 1). The ET-1 promoter is
also activated by phorbol myristate acetic acid or ectopic expression of
PKC-
1 in MC (32).
In summary, MC ET-1 release is under complex regulation, with
vasoconstrictor, profibrotic, inflammatory, and proliferative agents
augmenting its release, whereas vasorelaxant agents tend to inhibit its
production (Table 1). Because
MC ET-1 production is essentially regulated at the transcriptional level,
changes in its release and subsequent actions are relevant to sustained
biological effects rather than short-term and rapid modulation of glomerular
structure and function.
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ET-1 SIGNALING AND ACTIONS IN MCS
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ET-1 activates a variety of signaling systems in MCs to effect alterations
in cell contraction, hypertrophy, proliferation, and extracellular matrix
accumulation (Table 2). These
actions are subsequent to ET-1 binding to its heterotrimeric G protein-coupled
receptors, ET receptor A (ETRA) and B (ETRB), both of which are expressed by
MCs (32,
80,
103,
118). ET-1 binds to both
receptor subtypes with high affinity (Kd in the 100 pM
range) and typically exerts prolonged effects (up to several hours). Normal
plasma levels of ET-1 average 12 pM, indicating that the peptide
primarily functions as an autocrine or paracrine factor. This underscores the
importance of viewing MC ET-1 action in the context of the glomerular
microenvironment.
ET-1 receptors couple to members of the Gi, Gq, Gs, and
G
12/13 G protein families
(19,
43,
56) with resultant modulation
of a variety of signaling cascades, including cyclooxygenases, cytochrome
P-450, nitric oxide synthases (NOS), the nuclear helix-loop-helix
protein p8 (30),
serine/threonine kinases, and tyrosine kinases
(Fig. 2). Common to induction
of many of these pathways in MCs, ET-1 activates PLC
(49,
97,
98) and PKC
(94). Increased inositol
triphosphate levels are associated with cell alkalinization via augmented Na/H
exchange and increased intracellular Ca2+ concentration
([Ca2+]i)
(3,
94,
96,
97). The increase in
[Ca2+]i is due to release from intracellular
stores as well as influx from dihydropyridine-insensitive pathways
(94). Lower ET-1
concentrations (0.110 pM) cause slow, sustained increases in
[Ca2+]i that are dependent on
Ca2+ influx through a voltage channel-independent
mechanism, whereas higher ET-1 concentrations (
100 pM) cause a rapid and
transient increase that depends on Ca2+ release from
intracellular stores via activation of PLC and PKC
(97).

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Fig. 2. Schematic representation of ET-1 signaling in mesangial cells. The ET-1
receptor is coupled to Gi, Gq, Gs, and G proteins. PKC- ,
- , - , and - activation stimulates mesangial cell matrix
accumulation. Increased intracellular Ca2+ stimulates
nitric oxide synthase (NOS) production of NO as well as activation of
proline-rich tyrosine kinase 2 (Pyk2)-dependent signaling cascades. NO, via
activation of PKG, inhibits adenylate cyclase. Pyk2-mediated tyrosine
phosphorylation contributes to activation of p38 MAPK and cell contraction.
Activation of PKC and the Src family of kinases results in stimulation of the
ERK-signaling cascade, which controls induction of gene expression, important
for cell proliferation and hypertrophy. Tyrosine and serine phosphorylation of
adaptor protein Shc isoforms are crucial for the network of ET-1-mediated
signaling pathways. PI-3-K, phosphoinositol 3-kinase; COX, cyclooxygenase;
CaMK II, Ca2+/calmodulin-dependent protein kinase II;
AA, amino acid; PA, phosphatidic acid; IP3, inositol
1,4,5-trisphosphate.
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Hypertrophy and Proliferation
There is abundant evidence that ET-1 directly and indirectly (e.g., via
PDGF) (49) stimulates MC
mitogenesis (5,
28,
32,
80,
98) as well as partially
mediating the proliferative response to other growth factors (such as
angiotensin II) (5,
28). In fact, ET-1 stimulates
MC proliferation in an autocrine fashion because antisense oligonucleotides to
ET-1 reduce spontaneous MC proliferation in vitro
(67). The mitogenic effects of
ET-1 in MCs are likely primarily mediated via ETRA
(28,
105), although there are data
suggesting that activation of ETRB, as well as ETRA, in human MCs can induce
proliferation (32,
80)
(Fig. 3).

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Fig. 3. Schematic representation of biological effects mediated by endothelin
receptor A (ETRA) and endothelin receptor B (ETRB) in mesangial cells. The net
effect of ETRA activation is mesangial cell contraction, extracellular matrix
accumulation, and proliferation. The net effect of activation of ETRB tends to
be vasorelaxant as well as causing autostimulation of ET-1 production. AP-1,
activator protein-1; MMP-2, matrix metalloproteinase-2.
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ET-1 stimulation of MC proliferation involves several pathways, among which
MAPK figures prominently (83,
106). ET-1 induces activity
of all three major MAPK cascades in MCs: ERK1 and ERK2
(112), JNK/SAPK
(2), and p38 MAPK
(99). In addition, ET-1
stimulates expression of MAPK phosphatase 1 (MKP-1)
(23), a dual-specificity
phosphatase that downregulates MAPK signaling. There is convincing evidence
that ET-1 induces cell proliferation primarily via activation of the
Ras-Raf-Mek-ERK-signaling cascade
(92)
(Fig. 2). Late-onset, stable
changes in gene expression, associated with MC hypertrophy, were recently
reported to be controlled by ET-1-mediated activation of ERK, JNK/SAPK, and
phosphatidylinositol 3-kinase pathways
(30). In addition, ET-1
activation of ERK 1/2 is partially dependent on tyrosine phosphorylation of
the epidermal growth factor receptor and likely involves caveolin-1
(37). ET-1 induction of MAPK
and subsequent increased cyclin-dependent kinase 4 and cyclin D1 expression
occur through activation of ETRA
(45,
105).
ET-1 rapidly enhances tyrosine phosphorylation of proline-rich tyrosine
kinase 2 (Pyk2) and the Src family of cytoplasmic tyrosine kinases.
ET-1-induced activation of Pyk2 and Src results in tyrosine phosphorylation of
multiple signaling molecules, including recruitment of the adaptor proteins
Shc and Grb2 that ultimately lead to cell proliferation and/or hypertrophy
(Fig. 2). The ubiquitously
expressed adaptor protein Shc
(84), which exists in three
isoforms with relative molecular masses of 46, 52, and 66 kDa
(p46Shc, p52Shc, and p66Shc, respectively),
plays an important role in ET-1 signaling. ET-1 treatment of MCs results in
persistent tyrosine phosphorylation of p52Shc
(23), which promotes the
association of p52Shc with the Grb2/Sos complex due to recognition
of p52Shc P-Tyr by the Grb2 SH2 domain. The formation of the
trimolecular module Shc/Grb2/Sos localizes the guanosine exchange factor Sos
to GTPase Ras, causing the switch of RasGDP into the active GTP-bound form.
This initial activation of Ras is followed by rapid inactivation of Ras, as a
direct consequence of the MEK/ERK-dependent Sos1 phosphorylation and Sos1
release from the trimolecular module. Subsequent to Ras and ERK deactivation,
Sos1 reverts to the nonphosphorylated condition, enabling it to bind again to
the Grb2/Shc complex, which is stabilized by persistent Shc phosphorylation,
resulting in biphasic activation of Ras
(23). The second peak of ERK
activation is presumably attenuated by activation of a dual-specificity
phosphatase.
ET-1 also induces serine phosphorylation of p66Shc via
activation of the MEK/ERK-signaling module, resulting in p66Shc
association with the serine-binding, motif-containing protein
1433 (24).
Interestingly, p66Shc/ mice are resistant to
oxidative stress, and the p66Shc-mediated response to oxidative
stress is dependent on serine phosphorylation
(71). So far, ET-1 is among
few physiological agonists shown to induce serine phosphorylation of
p66Shc, raising the possibility that ET-1 is involved in cellular
resistance to oxidative stress.
Cell Contraction
ET-1 potently stimulates MC contraction, an effect that is independent of
dihydropyridine-sensitive Ca2+ channels and is likely
mediated through ETRA activation
(3,
91,
102). Pyk2 may play a crucial
role in ET-1-mediated contraction of MCs because 1) it is the only
cytoplasmic tyrosine kinase activated by mobilization of intracellular
Ca2+
(66); 2) tyrosine
phosphorylation appears to be essential for the contractile effects of many G
protein-coupled receptor ligands
(70,
108,
113,
122); 3) ET-1
stimulates Pyk2 autophosphorylation in a Ca2+-dependent
manner in MCs (99); and
4) Pyk2 is responsible for p38 MAPK activation in MCs, which has been
implicated in MC contraction
(99). It should be noted that
ET-1-mediated contraction also involves activation of the Rhi/Rho kinase
pathway because Rhi/Rho kinase inhibition markedly blunts ETRB agonist-induced
vasoconstriction (9).
ET-1-induced MC contraction may also involve Src tyrosine kinases, possibly
via
-arrestin-1-mediated recruitment of Src to a molecular complex with
the endothelin receptor (43)
and/or adhesion-dependent activation of Src via interaction with focal
adhesion kinase (FAK) (10).
ET-1 may activate Src, at least in part, via activation of
Ca2+/calmodulin-dependent protein kinase II (CaMK II) in
MCs (111)
(Fig. 2).
ET-1 stimulation of MC contraction may be modified by vasorelaxant
substances, particularly nitric oxide (NO) and PGE2. Activation of
ETRB increases cGMP via induction of NO, an effect that is dependent on
release of Ca2+ from intracellular stores and calmodulin
(81)
(Fig. 3). In contrast, ET-1
inhibits induction of cytokine-stimulated inducible NOS (iNOS) activity via
activation of ETRA (7,
33). ET-1 also stimulates
cyclooxygenase (COX) activity, resulting primarily in increases in
PGE2 with small increases in thromboxane A2
(95). This occurs via ETRA
induction of PLA2
(26) and COX-2
(38). COX-2 stimulation
depends on intracellular Ca2+ release, Ca-calmodulin
kinases, and nonreceptor-linked protein tyrosine kinase activity
(15) and is independent of PKC
(26). Recent studies also
demonstrate that ET-1 enhances nuclear factor of activated T cell
translocation to the nucleus in MCs and increases nuclear factor 2 of
activated T cell binding to the COX-2 promoter
(101).
Extracellular Matrix Accumulation
ET-1 increases fibronectin
(28,
82), type IV collagen
(28,
114), and type I collagen
(82) synthesis by MCs
(Table 2). In addition, ET-1
partially mediates angiotensin II-mediated MC extracellular matrix
accumulation (28). These
effects are primarily mediated via ETRA
(28,
55)
(Fig. 3) with resultant
activation of PKC-
, -
, -
, and -
(28,
114). Induction of
fibronectin and type I collagen synthesis appears to involve ERK2, but not JNK
or p38 MAPK (82).
ET-1 also seems to have a net inhibitory effect on extracellular matrix
degradation by MCs. Although ET-1 has been described to increase MC
collagenase (92) and matrix
metalloproteinase-2 activity (MMP-2)
(55), the peptide has been
shown to reduce fibrinolytic activity (via stimulation of plasminogen
activator inhibitor production)
(47), to reduce basal and
cytokine-stimulated MMP-2, and to enhance secretion of tissue inhibitor of
MMP-2 (117). These latter
effects are also mediated by activation of ETRA
(117)
(Fig. 3). Notably, mice
transgenic for the ET-1 promoter and gene develop marked glomerulosclerosis in
the absence of elevations in systemic blood pressure
(90).
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PATHOPHYSIOLOGY OF ET-1 IN MCS
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Glomerulonephritis
To demonstrate that MC-derived ET-1 is of pathogenic importance in
glomerulonephritis (GN), it is necessary to show that its production is
increased, that this results in a pathophysiological effect, and that blockade
of ET-1 action ameliorates disease severity. As discussed above, inflammatory
cytokines increase MC ET-1 release in vitro, suggesting that MC ET-1
production should be enhanced in GN. This has indeed been shown in animal
models: MC ET-1 production is increased in rat models of immune complex GN
(87), nephrotoxic serum
nephritis (120), and
mesangial proliferative GN
(119). In addition, MC ET-1
production is augmented in human systemic lupus erythematosis
(32), urinary ET-1 excretion
is proportional to the severity of human mesangial proliferative GN
(18), and
N-formyl-Met-Leu-Phe-stimulated neutrophils from patients with IgA
nephropathy stimulate rat MC ET-1 release more than neutrophils from patients
with non-IgA mesangial proliferative GN
(11).
As discussed earlier, there is abundant evidence that ET-1 increases MC
proliferation and matrix accumulation. ET-1 may further stimulate inflammation
because it elevates human MC production of TNF, ICAM-1, and VCAM-1
(14). Furthermore, ET-1
reduces TNF-mediated apoptosis in MCs (via induction of COX-2), potentially
causing additional cell accumulation
(46). That these effects of
ET-1 are of pathophysiological relevance is borne out by studies using ET
antagonists (Table 3). Indirect
evidence comes from studies in which either an angiotensin-converting enzyme
inhibitor (ACEI) (87) or a
thromboxane A2 receptor blocker
(120) reduced glomerular
injury in rat models of GN associated with decreased MC ET-1 levels. More
direct evidence is afforded by several studies. The ECE inhibitor CGS-26303
reduces MC expansion in puromycin aminonucleoside (PAN) nephrosis in rats
(22), and an ETRA antagonist,
FR-139317, reduces glomerular collagen
1(IV) and laminin
accumulation in PAN nephrosis
(20). In rat models of
mesangial proliferative GN, FR-139317 reduced MC proliferation, combined
ETRA/ETRB blockade with bosentan improved renal function and reduced MC ET-1
mRNA levels (27), and
antisense oligonucleotides to ET-1 decreased MC proliferation and matrix
expansion (67). Thus there is
strong evidence that MC-derived ET-1 plays a significant pathogenic role in
GN.
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Table 3. Effects of ET blockers on mesangial cell and glomerular dysfunction in
experimental rat models of renal disease
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Diabetes Mellitus
Although there is no direct evidence in vivo that MC ET-1 production is
increased in diabetic nephropathy, there are in vitro data suggesting that MC
ET-1 synthesis is increased by hyperglycemia. Furthermore, hyperglycemia
modifies MC responses to ET-1. For example, ET-1-stimulated p38 MAPK and
cAMP-responsive element-binding protein phosphorylation in MCs is enhanced by
hyperglycemia (109). In
addition, hyperglycemia augments ET-1-stimulated
1(IV)
collagen production in MCs, an effect that requires PKC-
, -
,
-
, and ERK1/2, as well as PKC-
and -
(latter independent of
ERK1/2) (36). Interestingly,
hyperglycemia decreases the MC ET-1 Ca2+ signal through
decreased receptor-operated Ca2+ influx
(79), an effect that could
explain hyperglycemic inhibition of ET-1-induced MC contraction
(16).
There is abundant evidence in vivo that ET-1 antagonists ameliorate
glomerular injury in animal models of diabetic nephropathy
(Table 3). ET-1 blockade with
combined ETRA/ETRB inhibition (bosentan) reduced albuminuria and increased
glomerular filtration rate (GFR)
(12) and ameliorated mesangial
matrix, fibronectin, and
2(IV) collagen accumulation in
diabetic rats (13). In
addition, combined receptor blockade with LU-224332 for 36 wk prevented
fibronectin and collagen IV accumulation in diabetic rats
(35). The beneficial effects
of combined blockers may be largely a result of ETRA blockade because
1) ETRA blockade with YM-598 reduced albuminuria in a diabetic rats
(100); 2) ETRA
blockade with LU-135252 for 6 mo reduced glomerular histological injury in
rats with streptozotocin-induced diabetes
(17); and 3) ETRA
blockade with FR-139317 for 24 wk decreased glomerular mRNA levels of
collagen, laminin, TGF-
, basic FGF, and PDGF-B in diabetic rats
(75). Taken together, these
studies suggest that MC ET-1 production is enhanced in diabetic nephropathy
and that excessive ET-1 action in the diabetic glomerulus can cause enhanced
matrix accumulation, proteinuria, and reduced GFR.
Hypertensive Glomerulosclerosis
MC ET-1 production may be elevated in hypertension. MC ET-1 levels are
higher in spontaneously hypertensive (SHR) rats than in nonhypertensive
controls (64), whereas MC ETRA
mRNA levels are higher in stroke-prone SHR compared with normotensive
Wistar-Kyoto (WKY) rats (34).
Several agents also enhance MC ET-1 release more from SHR than WKY animals,
including angiotensin II, phorbol ester, vasopressin, thrombin, and PDGF
(41,
42). Relevant to these latter
findings is the observation that ACEI reduced ET-1 production by MCs from
uninephrectomized SHR rats
(64). Although data are
limited on the role of MC ET-1 in hypertensive glomerular injury, one study
found that bosentan reduced glomerular extracellular matrix accumulation in
NG-nitro-L-arginine methyl ester-induced
hypertensive mice despite the lack of an effect on blood pressure
(8). This study also found that
bosentan normalized the activity of an
1(I) collagen
promoter-luciferase transgene in these mice. Thus initial studies suggest that
MC-derived ET-1 may also play a role in hypertensive glomerulosclerosis.
Acute and Chronic Renal Failure
Data on MC ET-1 production or actions in chronic renal failure outside of
the specific examples above are few, although there is abundant evidence that
ET-1 plays a role in the progression of renal insufficiency
(54,
57). There is also little
information on MC-derived ET-1 in acute renal failure. Numerous studies have
shown that ET-1-induced vasoconstriction is of pathogenic importance in
various forms of acute renal failure
(78); however, it is unclear
whether this ET-1 substantially derives from MCs. Agents that induce renal
vasoconstriction and/or cause acute renal failure can stimulate MC ET-1
release, including cyclosporin, FK506, myoglobin, thromboxane A2,
angiotensin II, vasopressin, and reactive oxygen species
(29,
39,
53,
59,
62,
88,
121). It is conceivable that
MC-derived ET-1 in the setting of acute renal failure reduces the glomerular
ultrafiltration coefficient by eliciting MC contraction or even contributes to
downstream efferent arteriolar vasoconstriction; however, these considerations
are entirely conjectural.
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ET ANTAGONISTS IN THE CLINICAL SETTING
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Given the strong indictment of MC ET-1 overactivity in the pathogenesis of
the three leading causes of end-stage renal disease, namely, diabetes,
hypertension, and glomerulonephritis, there is cause for considerable
excitement about the used of ET-1 blockers in the treatment of these diseases.
With the recent Food and Drug Administration approval of an ET antagonist for
treatment of primary pulmonary hypertension, the stage is now set for
realistic consideration of the use of this class of agents in treating kidney
disease. To date, there have been no clinical studies that have addressed this
issue; however, studies of other diseases provide an impetus for the
translation of ET blockers to the therapy for renal disease. This section will
review the present status of ET antagonists in the clinical setting, focusing
on the cardiopulmonary system. While this material does not cover diseases of
the kidney, we thought it important at this time to emphasize the work being
done in other organ systems, hopefully as an impetus for similar studies to be
conducted in renal disease.
Initial studies focused on the effects of oral combined ETRA/ETRB blockade
with generally disappointing results. One of the earliest studies was a phase
II trial examining the effect of 4 wk of therapy with the combined
ETRA/ETRB-receptor antagonist bosentan on blood pressure in 293 patients with
mild to moderate essential hypertension
(63). Blood pressure decreased
modestly, and there were a significant number of side effects, including
headache, flushing, leg edema, and reversible elevations in liver enzymes
(LFTs). Bosentan was then used in a trial of 370 patients with New York Heart
Association (NYHA) class IIIb/IV congestive heart failure (CHF), the so-called
Research on ET Antagonism in CHF trial
(74). The trial was
discontinued prematurely because of elevations in LFTs; however, it appeared
that bosentan initially worsened CHF but may have slightly improved the
outcome after 6 mo. Subsequently, a lower dose of bosentan was administered to
1,613 patients with NYHA class IIIb/IV CHF in the ET Antagonist Bosentan for
Lowering Cardiac Events in Heart Failure trial (ENABLE1 in Europe and ENABLE2
in North America) (51).
Unfortunately, no difference was detected between bosentan and placebo on
all-cause mortality or hospitalization for CHF. Another trial, the Enrasentan
Clinical Outcomes Randomized study, using a combined ETRA/ETRB antagonist,
found that ET blockade increased heart failure events in 419 patients with
NYHA class II/III CHF (85). An
intravenous ETRA/ETRB blocker, tezosentan, has been given in a trial involving
285 patients with acute decompensated CHF (RITZ-2), and there was decreased
pulmonary capillary wedge pressure and increased cardiac output
(68). Unfortunately, a
follow-up study (RITZ-5) found no affect of tezosentan on the outcome of acute
pulmonary edema (52). Another
phase II study, using TAK-044, a combined ETRA/ETRB blocker, found no
difference in clinical outcomes in patients with aneurysmal subarachnoid
hemorrhage (89). The most
encouraging results using combined ETRA/ETRB blockers have been in pulmonary
hypertension. Bosentan modestly increased exercise capacity in 213 patients;
however, 9 patients stopped the drug because of side effects
(86). Finally, there is a case
report of a patient with systemic sclerosis whose digital ulcers and cutaneous
fibrosis substantially improved with 1 yr of bosentan therapy
(40). In summary, the clinical
trials with ETRA/ETRB combined blockade in cardiopulmonary disease have either
been unpromising or shown only a modest benefit.
ETRA-specific antagonists could be potentially superior to combined
blockers by virtue of avoiding inhibition of NO, or other factor, production
as a result of ETRB blockade. To date, relatively few clinical studies have
been performed using these agents. Treatment with darusentan (LU-135252) for 6
wk reduced mean blood pressure (up to 11 mmHg) in a trial of 392 patients with
moderate essential hypertension
(76). A 3-wk trial (HEAT) with
oral darusentan in 157 patients with NYHA class III CHF showed improved
cardiac index and reduced systemic vascular resistance, with no change in LFTs
(69). Treatment with
sitaxsentan for 12 wk in 20 patients with NYHA class II-IV pulmonary
hypertension improved exercise capacity
(6). Interestingly, a phase II
study using ETRA blockade in patients with prostate cancer (prostate cancer
cell lines express very high levels of ETRA) is underway
(85).
Finally, agents are being developed that inhibit ET actions as well as
affect other systems. BMS-248360, a potent inhibitor of ETRA and
AT1 receptors, has recently been described
(73). ECE inhibitors have been
designed, although they have not been clinically tested. Because ECEs share
37% sequence homology with neutral endopeptidase (NEP), which degrades atrial
natriuretic peptide and bradykinin, dual ECE and NEP inhibitors have been
designed. One such dual inhibitor, CGS-26303, reduces glomerular lesions in
rats with PAN nephrosis (22).
Even triple inhibitors (ECE, NEP, and ACE) have been designed: all three
enzymes are zinc metalloproteases and can be inhibited by groups that interact
with the zinc-binding domain (e.g., sulfhydryl groups). One such triple
inhibitor, SCH-54470, decreased blood pressure and proteinuria and increased
GFR in the remnant kidney rat model
(110). Last, vasopeptidase
inhibitors (inhibiting ACE and NEP) have been designed (e.g., omapatrilat);
however, their clinical utility is uncertain
(107). Notably, inhibition of
NEP can result in elevated ET-1 levels because this metalloprotease degrades
ET-1.
In summary, the stage is set for clinical trials of ET inhibitors in
patients with glomerular disease characterized by increased ET-1 production
and actions. The challenges include finding an agent with tolerable
therapeutic indexes, targeting ET receptors that most likely are pathogenic
(likely ETRA), and, most of all, meeting the challenges of conducting studies
whose benefit may only be truly known after long-term drug administration.
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CONCLUSION
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In conclusion, abundant evidence points to a pivotal role for ET-1 in the
biology, and particularly the pathology, of the renal mesangium. The peptide
is produced by MCs and can, in turn, act on MCs to elicit proliferation,
hypertrophy, contraction, and/or extracellular matrix accumulation. These
effects are mediated in large part through activation of ETRA and particularly
involve PKC and MAPK. Excessive ET-1 production by, and action on, MCs is of
pathogenic importance in glomerular damage in animal models of GN, diabetes,
and hypertension. With the emergence of Food and Drug Administration approval
of clinical ET antagonists, the time is propitious for clinical trials using
ET antagonists in these renal diseases. While challenges exist with such
trials, it is our contention that the preclinical studies are so strongly
indicative of a potential beneficial effect of these agents in glomerular
disease that this challenge should be aggressively pursued.
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DISCLOSURES
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This work was supported by National Institutes of Health Grants DK-59047
(D. E. Kohan), HL-22563 (A. Sorokin), and DK-41684 (A. Sorokin).
 |
FOOTNOTES
|
---|
Address for reprint requests and other correspondence: D. E. Kohan, Div. of
Nephrology, Univ. of Utah Health Sciences Ctr., 1900 East, 30 North, Salt Lake
City, UT 84132 (E-mail:
donald.kohan{at}hsc.utah.edu).
The costs of publication of this article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section 1734
solely to indicate this fact.
 |
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