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Natriuretic Peptide Receptors in the Human Endolymphatic Sac
John L. Dornhoffer, MD;
Christopher Danner, MD;
Shulin Li, PhD
Arch Otolaryngol Head Neck Surg. 2002;128:379-383.
ABSTRACT
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Objective To examine human endolymphatic sac (ELS) tissue for atrial natriuretic
peptide (ANP) receptor subtypes A, B, and C.
Design Pilot study.
Methods Immunohistochemical analysis of human ELS tissue specimens. The ANP
receptors were characterized using the peroxidase/antiperoxidase method and
polyclonal antibodies directed against each receptor subtype. The identity
of the stain regarding receptor subclass was masked from the observer. Human
kidney tissue known to contain all 3 receptor subtypes was used as a control.
Presence of the receptor subclasses was confirmed using reverse transcriptase–polymerase
chain reaction (RT-PCR) techniques.
Subjects Samples of ELS tissue were obtained at autopsy from 3 fresh cadaver
specimens (6 ears) and as surgical specimens from 3 patients (1 for immunohistochemical
analysis and 2 for RT-PCR) undergoing acoustic neuroma resection using the
translabyrinthine approach.
Results The ANP type B receptors demonstrated moderate to strong reactivity
in all 7 specimens, and mild to moderate staining to the ANP type C receptor
was also noted. No appreciable reactivity to the ANP type A receptor was detected
using immunohistochemical techniques. All 3 receptor subclasses were detected
using RT-PCR.
Conclusions The ANP receptors are found within the human ELS, with a predominance
of ANP type B based on the intensity of staining. The ANPs may be involved
in fluid homeostasis in the inner ear. Based on these findings, C-type natriuretic
peptide may be a more effective peptide within the human ELS for fluid regulation
because its binding affinity is virtually exclusive for the ANP type B receptor.
INTRODUCTION
FLUID HOMEOSTASIS in the endolymphatic system of the inner ear is essential
for normal hair cell function, but the mechanisms involved with its maintenance,
to date, are poorly understood. It is believed that endolymph is produced
by active transport of electrolytes in the stria vascularis of the cochlea
and the dark cell epithelium of the vestibular organ and that it is subsequently
reabsorbed by the endolymphatic sac (ELS).1
The ELS epithelium synthesizes and secretes certain complex molecules, including
hyaluronan, into the ELS lumen and is postulated to be involved in the sensitive
regulation of endolymphatic volume and pressure.2
Thus, dysfunction of the ELS is thought to be the underlying cause of the
endolymphatic hydrops associated with Meniere's disease, a disease with no
accepted cure.1
Research3-5
has suggested a possible role of atrial natriuretic peptides (ANPs) in the
regulation of inner ear fluid. The ANPs are a group of hormones originally
identified in mammalian atrial cardiocytes in the early 1980s.6-8
They are known to exert a smooth muscle effect, with vasodilation, diuretic,
and natriuretic activities in the kidney. The natriuretic peptide system comprises
at least 3 known peptides—ANP, brain natriuretic peptide (BNP), and
C-type natriuretic peptide (CNP)—and 3 receptor subtypes. Two of the
receptors, ANP type A (ANP-A) and ANP type B (ANP-B), represent the bioactive
receptors, whereas ANP type C (ANP-C) is biologically inactive and serves
as a clearance receptor. Natriuretic peptides have been located in other extracardiac
sites, such as the adrenal cortex, lung parenchyma, gallbladder, ciliary body
of the eye, and choroid plexus of the brain.9-13
Investigators3-5
have demonstrated the presence of ANP receptors in the inner ear of the guinea
pig, with ANP-like immunoreactivity demonstrated in the cochlea, the secretary
epithelium of the vestibular organ, and the ELS. The results of these animal
studies suggest that the inner ear may have paracrine or autocrine activity
for the regulation of labyrinthine fluids and electrolytes. The purpose of
this study was to characterize specific ANP receptor subtypes within the human
ELS using immunohistochemical techniques, with confirmation by reverse transcriptase–polymerase
chain reaction (RT-PCR).
MATERIALS AND METHODS
SPECIMEN COLLECTION
Human ELSs were obtained from 3 fresh cadaver specimens (6 ears) and
from 3 patients undergoing a translabyrinthine approach for acoustic neuroma
resection (1 for immunohistochemical analysis and 2 for RT-PCR). Patients
gave informed consent for the study, which had received approval by the institutional
review board at the University of Arkansas for Medical Sciences, Little Rock.
The entire ELS was removed en bloc with a portion of posterior fossa bone
and otic capsule. Control samples consisted of human kidney tissue known to
contain all 3 receptor subtypes.
IMMUNOHISTOCHEMICAL ANALYSIS
Specimens were placed in 10% neutral buffered formaldehyde, followed
by decalcification in formic acid. After completion of decalcification (10-14
days), the samples were embedded in paraffin. The specimens were then serially
sectioned (4-5 µm) parallel to the long axis of the ELS, fixed, and
mounted on appropriately labeled slides. The sections were hydrated in the
usual manner, terminating in phosphate-buffered saline solution.
Tissue sections were incubated in 3% hydrogen peroxide and phosphate-buffered
saline solution to block endogenous peroxidase activity. Polyclonal antibodies
(rabbit and antirat) directed against the ANP-A, ANP-B, and ANP-C receptors
were obtained from David Garbers, MD, Southwestern Medical Center, University
of Texas, Dallas.14 Each individual clone was
incubated with the specimens at concentrations of 1:100 and 1:1000. The 1:1000
dilution was used for analysis because it gave the best staining with the
least background activity. Steam was used to increase antigen retrieval in
half of the specimens, but no significant difference was seen with this technique.
The specimens were then incubated with diaminobenzidine–hydrogen peroxide,
which reacts with the peroxidase-antibody complex to produce a red-brown stain.
The slides were counterstained with Mayer hematoxylin to visualize the nuclei
and were studied with conventional light microscopy.
Technique controls were performed for each specimen using the same method
but omitting the antibody step. Representative slides from each specimen set
were also stained with hematoxylin-eosin for additional light microscopic
study. For each sample, the identity of the stain regarding receptor subclass
was masked from the observer to minimize observer bias in quantifying relative
staining intensity compared with background staining.
RT-PCR ANALYSIS
To confirm the presence of the subclasses of ANP receptor genes in human
ELS specimens, RT-PCR analysis was performed on 2 ELS specimens obtained at
surgery during resection of acoustic neuromas using the translabyrinthine
approach. Each sample was placed in liquid nitrogen. Human kidney tissue samples
were used as a positive control. To isolate RNA for RT-PCR, the harvested
tissues were retrieved from the liquid nitrogen and homogenized using a Polytron
homogenizer (Brinkmann Instruments, Inc, Westbury, NY). Reagent (TRIzol; Gibco,
Grand Island, NY) was added at a concentration of 1 mL per 100 to 200 mg of
tissue, and the material was spun at 14 000 rpm for 10 minutes. The supernatant
was transferred to a new tube, mixed with 200 µL of chloroform, and
spun. The supernatant was then isolated and mixed with 500 µL of 2-propanol.
The material was cooled to -20°C for 30 minutes and then spun at
14 000 rpm for 20 minutes. The pellet was washed twice with 75% ethanol
and then dissolved in 20 to 100 µL of DEPC-H2O. Optical density
was measured at 260 nm to obtain the RNA concentration. The RNA was then purified
by DNase treatment. A total of 30 µg of RNA in 51 µL of DEPC-H2O was mixed with 10 x DNase I buffer (6 µL) and 1 U/µL
of DNase I (3 µL) (Clontech, Palo Alto, Calif) and incubated at 37°C
for 30 minutes. To this was added 10 x termination buffer (6 µL),
followed by 66 µL of phenol-chloroform (1:1). The solution was spun
at 14 000 rpm for 10 minutes. The supernatant was isolated, mixed with
66 µL of chloroform, and spun at 14 000 rpm for 10 minutes. The
top aqueous layer was transferred and mixed with a one-tenth volume of 3M sodium acetate and 2 volumes of ethanol and cooled for
30 minutes on ice. The mixture was spun, and the pellet was washed and then
dissolved in DEPC-H2O. This yielded 10 to 20 µg of purified
RNA.
Reverse transcriptase–polymerase chain reaction was performed
using a commercially available reverse transcription procedure (First-Strand
cDNA Synthesis; Amersham Pharmacia Biotech, Piscataway, NJ). A total of 5
µg of RNA in 33 µL of DEPC-H2O was heated at 65°C
for 10 minutes and then chilled on ice for 2 minutes. The RNA solution was
transferred to a tube containing First-Strand Reaction Mix Beads (Amersham
Pharmacia Biotech); 2 µL of random primer was added, and the contents
were mixed by gentle vortex and then incubated at 37°C for 60 minutes.
The total volume of first-strand complementary DNA was 35 µL. Using
complementary DNA as a template, the primers of the ANP-A, ANP-B, and ANP-C
receptors were designed as follows:
- ANP-A receptor (length: 500 base pair [bp]): sense,
5'-AACCTGACGGTAGCCGTGGTAC-3'; antisense, 5'-TGCTCCTTCTTCGTCACGAGA-3'
- ANP-B receptor (length: 454 bp): sense, 5'-ATGGCGCTGCCATCACTTCT-3';
antisense, 5'-ACTCACCCAGCTTGGGAGCA-3'
- ANP-C receptor (length: 579 bp): sense, 5'-ACGATGCCGTCTCTGCTGGT-3';
antisense, 5'-CCTTGTCCCGCTCGTAGTAG-3'
- Reduced glyceraldehyde-phosphate dehydrogenase
(length: 354 bp): sense, 5'-AGGCTGAGAATGGGAAG-3'; antisense, 5'-AGTACTCGGGAAGGTGC-3'
The PCR conditions were as follows: denaturation at 94°C for 2 minutes,
followed by 37 cycles of 94°C for 30 seconds, 57°C for 1 minute, and
72°C for 1 minute. The PCR mixture was incubated for 10 minutes at 72°C
after the amplification cycles and then stored at 4°C or used immediately
for electrophoresis.
RESULTS
The entire ELS was identified in all cases. Moderate-to-strong staining
in the epithelium of the ELS was demonstrated to the ANP-B receptor in all
7 samples. Staining of the ANP-B receptor was present throughout the ELS but
had the highest concentration in the rugose portion (Figure 1B). All samples showed slight-to-moderate staining to the
ANP-C receptor in the epithelium, with a distribution similar to that of the
ANP-B receptor (Figure 1C). No appreciable
staining was noted for the ANP-A receptor subclass (Figure 1A). Control specimens demonstrated positive staining for
all 3 receptor subtypes in the kidney tissue, and the technique controls appropriately
had negative findings.
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Figure 1. Staining of atrial natriuretic
peptide (ANP) receptors in the endolymphatic sac. Polyclonal antibodies against
ANP types A (A), B (B), and C (C) were incubated with each sac specimen at
a concentration of 1:1000. Specimens were incubated with diaminobenzidine–hydrogen
peroxide and counterstained with Mayer hematoxylin to visualize the nuclei
(original magnification x200).
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The results of RT-PCR confirmed that all 3 receptors could be detected
in the human ELS sample (see Figure 2
for RT-PCR of human ANP-B).
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Figure 2. Reverse transcriptase–polymerase
chain reaction (RT-PCR) of human atrial natriuretic peptide type B from the
patient sample. Lane 1, PCR with RNA without RT; lane 2, PCR after RT. The
primer used for RT is oligodeoxythymidine, and the primers used for PCR are
5'-ATG GCG CTG CCA TCA CTT CT-3' (sense primer) and 5'-ACT
CAC CCA GCT TGG GAG CA-3' (antisense primer).
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COMMENT
Although the ELS was once thought to represent a vestigial organ of
embryogenesis, it is now known to have an essential role in inner ear homeostasis.
Systemic administration of hypertonic agents, such as glycerol, has been shown
to provoke a transient improvement in hearing in patients with the endolymphatic
hydrops associated with Meniere's disease through mechanisms that were initially
unclear.15 More recent research2
in animals has demonstrated morphologic changes in the ELS associated with
the systemic administration of glycerol, including increased metabolic activity,
with the secretion of osmotically active glycoproteins into the lumen of the
sac and subsequent lysis and breakdown of these substances. It has thus been
suggested that the ELS affects fluid homeostasis in the endolymph system through
modulation of the osmotic milieu of this space, with secretion of osmotically
active substances into its lumen.16 The exact
mechanism through which the ELS regulates this system is unknown, but it is
postulated to involve a locally effective paracrine system, possibly involving
the cochlear duct or stria vascularis. Dysfunction of the ELS or breakdown
of this system is believed to result in the endolymphatic hydrops of Meniere's
disease.1
Results of recent studies3-5
have shown that ANPs and ANP-like receptors exist in the inner ear. Their
involvement with fluid homeostasis in other organ systems indicates that they
could be involved in normal inner ear fluid regulation. Our current understanding
of natriuretic peptides, their specific receptors, and their natriuretic,
diuretic, and vasodilator effects are the result of numerous studies already
performed on cardiac and renal tissue.6-8,17
Myocardiocytes seem to be the major site of synthesis and secretion for ANP;
however, immunohistochemical activity of ANP has been observed in a variety
of extracardiac tissues, such as the brain, kidney, adrenal medulla, salivary
glands, ciliary process of the eye, and anterior pituitary gland.9-13
Brain natriuretic peptide and CNP, first isolated from porcine brain tissue,
have also been located in other sites, including the heart (BNP),18 kidney (CNP),19 and
gastrointestinal tract (CNP).19
Three types of natriuretic peptide receptors have been identified and
characterized. Two of these, ANP-A and ANP-B, represent the bioactive receptors,20-21 and they consist of an extracellular
domain for natriuretic peptide binding, a single transmembrane domain, a single
adenosine triphosphate–binding domain for natriuretic peptide binding,
and a guanylyl cyclase moiety.22 By activating
guanylate cyclase, intracellular cyclic guanosine monophosphate concentrations
increase and serve as a second messenger at the cellular level in various
target tissues.23 Recently, a third receptor,
ANP-C, has been identified.24 The ANP-C receptor,
which is not coupled to guanylate cyclase, is thought to be biologically silent
and to serve as a specific clearance binding site for natriuretic peptides.25 The 3 natriuretic peptides exhibit different binding
affinities to the 3 receptor subtypes.26 The
ANP-A receptors preferentially bind ANP over BNP, with little reactivity for
CNP. The ANP-B receptors seem to be highly selective for CNP, with an affinity
that is 50- to 500-fold higher than for ANP or BNP. The ANP-C receptors bind
all 3 natriuretic peptides, but with a rank order of ANP>BNP>CNP.
Based on the knowledge that natriuretic peptides are located within
extracardiac tissues known to play a role in the maintenance of fluid/electrolyte
homeostasis (ie, ciliary process of the eye and choroid plexus of the cerebral
ventricles), it has been postulated that they may also be present in the inner
ear and have similar activity. In the late 1980s, Lamprecht and Meyer zum
Gottesberge and their colleagues3-4
demonstrated the presence and localization of ANP receptors within the inner
ear of the guinea pig. Using autoradiographic techniques with radiolabeled
ANP/cardiodilantin, receptors were localized to the stria vascularis, the
organ of Corti, spiral ganglion cells, and the epithelial layer of the pars
rugosa of the ELS. Results of additional studies5, 27
have also confirmed the presence of peptide receptors in the inner ear. Results
of a study by Rachel et al28 showed that infusion
of ANP directly into the inner ear of guinea pigs contributes to the regulation
of vestibular blood flow. Results of a more recent study29
suggest that epithelial cells of the ELS contain an endogenous hormone, tentatively
named "saccin," that exerts a strong natriuresis. In 1997, Krause et al30 identified the presence of ANP-A and ANP-B receptor
subtypes within inner ear tissue obtained from guinea pigs using RT-PCR. They
also identified a new guanylyl cyclase receptor, GC-C, which is normally present
in the intestines. Their PCR analysis did not demonstrate the presence of
any clearance receptors (ANP-C).
To our knowledge, this study is the first to identify specific natriuretic
peptide receptors within the human ELS. The combination of immunohistochemical
and PCR techniques confirmed the presence of all 3 receptor subclasses, with
an apparent predominance of the ANP-B receptor based on intensity of staining
with immunoperoxidase. The ANP-A receptor seemed to be present based on the
sensitive, but nonquantitative, RT-PCR, but the expression of this receptor
was apparently low based on the inability to detect it against background
staining using the less sensitive immunoperoxidase techniques.
These findings imply that CNP, not ANP, may be a more effective peptide
within the human ELS for fluid regulation because its binding affinity is
virtually exclusive for the ANP-B receptor, which showed the strongest reactivity.31-32 Earlier studies showed only minimal
immunoreactivity when using radiolabeled ANP,4
suggesting that few if any receptors were present within the ELS. This information
is consistent with our data because ANP is known to have weak affinity for
the ANP-B receptor, the predominant subtype demonstrated in this study.26 C-type natriuretic peptide was first isolated from
porcine brain in 1990, and it is the major natriuretic peptide in human cerebrospinal
fluid.17, 33 Results of previous
studies33 have shown that CNP stimulates excretion
of sodium and water from the kidney and thereby suggest that it may also play
a role in the regulation of water and electrolyte homeostasis within the inner
ear.
The findings reported herein lend some credence to the hypothesis that
fluid homeostasis in the endolymphatic system could be regulated by a locally
effective paracrine system involving the ANP system, analogous to other organ
systems in the body. The exact mechanism of action has not been elucidated
but intuitively would involve either regulation of fluid production by the
stria vascularis or absorption by the ELS.28
It has been suggested that the ELS affects fluid homeostasis in the endolymphatic
system through modulation of the osmotic milieu of this space, with the secretion
of osmotically active substances into its lumen; however, the mechanism of
action is unknown.16 It is conceivable that
ANPs could be involved in this mechanism. It is likewise possible that the
ANP system could be involved in fluid production by the stria vascularis.28 The natriuretic properties of ANPs in the kidney
are well-known, and their association with excretory organs such as the gallbladder
and choroid plexus supports this notion. Although ANP receptors have been
demonstrated in the inner ear, their association with fluid transport in the
endolymphatic system is, at this point, only conjecture. Animal studies are
currently ongoing at this institution (Department of Otolaryngology/Head and
Neck Surgery, University of Arkansas for Medical Sciences) to investigate
these unique peptides and to define their role within the inner ear.
In conclusion, (1) the natriuretic peptide receptors are found within
the human ELS, with a predominance of ANP-B based on the intensity of staining;
(2) the ANP system may be involved in fluid homeostasis in the human endolymphatic
system; and (3) CNP, rather than ANP, may be a more effective peptide within
the human ELS for fluid regulation because its binding affinity is virtually
exclusive for the ANP-B receptor.
AUTHOR INFORMATION
Accepted for publication September 14, 2001.
This study was funded by a grant from the National Organization for
Hearing Research, Narberth, Pa.
This study was presented at the Ninth International Symposium and Workshops
on Inner Ear Medicine and Surgery, Aspen, Colo, March 12, 2000.
We thank Mary K. Dornhoffer for her editorial assistance during the
preparation of the manuscript.
Corresponding author and reprints: John L. Dornhoffer, MD, Department
of Otolaryngology/Head and Neck Surgery, University of Arkansas for Medical
Sciences, 4301 W Markham, MS 543, Little Rock, AR 72205 (e-mail: DornhofferJohnL{at}uams.edu).
From the Department of Otolaryngology/Head and Neck Surgery, University
of Arkansas for Medical Sciences, Little Rock.
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