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From INSERM U423*
and the Département deGénétique et Unité INSERMU393,
Hôpital Necker-Enfants Malades,Paris, France; the Division of Nephrology,
Johns Hopkins University School of Medicine, Baltimore, Maryland; theDepartment of Internal Medicine,
Section ofNephrology, Yale University, New Haven, Connecticut; and the Divisionof Nephrology,¶
University of Louvain MedicalSchool, Brussels, Belgium
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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The vast majority of ADPKD cases (85%) are linked to PKD1.
The PKD1 gene encodes a large protein (
450 kd),
polycystin-1, thought to be involved in cell-cell or cell-matrix
interactions.2-4
The extracellular domain of polycystin-1
contains a region of homology with a sea urchin protein (the receptor
for egg jelly, REJ) that is implicated in ion movements leading to
conformational changes before fertilization.8
The
cytoplasmic tail of polycystin-1 may bind heterotrimeric G proteins
in vitro,9
activate the transcription factor
AP-1,10
and have a role in modulating Wnt
signaling.11
Recently, using MDCK cells expressing the
human PKD1 gene, it has been shown that polycystin-1
down-regulates proliferation and induces resistance to
apoptosis.12
The PKD2 gene is mutated in more than 10% of ADPKD cases. It encodes polycystin-2, which shares similarity with polycystin-1, voltage-activated calcium, and transient receptor potential (TRP) channel subunits.5 Interaction between polycystin-2 and the TRP protein TRPC1 has been shown in vitro.13 Polycystin-2 is predicted to form homomultimers and/or heteromultimers, especially with polycystin-1 via coiled-coil domains in their cytoplasmic regions,14,15 suggesting that these two proteins interact in a common signaling pathway. Furthermore, it was recently shown that co-assembly of polycystin-1 and polycystin-2 in CHO cells produces a unique channel activity.16
In ADPKD kidneys, cysts originate from only a small number of nephrons. Studies of renal17,18 and hepatic cysts19 in PKD1 as well as in PKD220,21 patients, suggest a two-hit molecular mechanism for their focal occurrence, making ADPKD a recessive disease at the cellular level. More recently, it has been reported that somatic mutations may affect PKD2 in ADPKD1 cysts, or PKD1 in ADPKD2 cysts, leading to a trans-heterozygous status.22,23
Previous reports have shown that PKD1 and PKD2 transcripts are widely expressed in most tissues.5,24 However, the localization of transcripts in human kidneys is unknown and the distribution of the proteins, especially of polycystin-1 is still debated.25 The knowledge of their precise distribution could help to clarify their role and the mechanism of cyst formation. Here we report the expression patterns of human PKD1 and PKD2 transcripts and their encoded proteins using Northern blot analysis, in situ hybridization, and immunohistochemical methods. The study was performed on normal embryos, and normal fetal and postnatal kidneys.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Ten normal fetal kidneys (10 to 38 weeks) and fetal extrarenal
tissues from two fetuses (16 and 19 week) were obtained at autopsy
after spontaneous abortion or termination of pregnancy for medical
reasons (Table 1)
. Two morphologically
normal intact embryos (5 and 6 weeks) were obtained after legal
abortion by Mifepristone (RU486) performed at the Hôpital
Broussais (Paris, France). Written maternal consent was obtained after
information about the research project was given and the abortion had
been performed. The entire procedure was approved by INSERM and the
ethics committee. Normal mature kidneys not used for transplantation
and the tumor-free pole of a kidney removed for polar carcinoma were
also used for the study. Specimens were immediately snap-frozen in
liquid nitrogen and stored at -80°C until use, or fixed in 4%
paraformaldehyde before embedding. Embryos were fixed in 4%
paraformaldehyde in phosphate-buffered saline solution, microdissected
from the whole trophoblast, dehydrated, and embedded in paraplast
before sectioning. Normal kidney specimens were also snap-frozen for
Northern blot analysis.
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DNA probes corresponding to a gel-purified 368-bp
XhoI/BamHI-digested fragment and 850-bp
EcoRI/NotI-digested fragments of pLig2-1 and
XF-75, respectively, were synthesized using the random primers
DNA-labeling system (Life Technologies, Inc., Gaithersburg, MD) with
[
-32P]dCTP (Amersham Pharmacia Biotech,
Buckinghamshire, UK). Total RNA was isolated with the RNeasy Maxi Kit
(Qiagen, Hilden, Germany) from fetal and adult kidneys. These filters
and Human Multiple Tissue Northern Blots (no. 7756-1 and no. 7760-1)
(Clontech, Palo Alto, CA) were hybridized at 68°C with cDNA probes
made as described above, according to the manufacturer’s instructions
(Clontech). The cDNA used as template for probe synthesis was verified
by sequencing before utilization for Northern blot analysis and
in situ hybridization.
In Situ Hybridization
A portion of PKD1 cDNA corresponding to bp 11409 to
11771, located in the specific portion of the gene,4,5
was
amplified by polymerase chain reaction and subcloned into the vector
pCRII (Invitrogen, San Diego, CA). The resulting construct is
designated pLig2-1. For in situ hybridization, pLig2-1 was
linearized by XhoI or BamHI digestion for the
anti-sense and sense riboprobes, respectively. The 368-bp anti-sense
and sense riboprobes were synthesized using Sp6 and
T7 RNA polymerase (Boehringer-Mannheim, Mannheim, Germany),
respectively, with [35S]UTP
(35S-UTPS, Amersham) according to the
manufacturer’s instructions. A portion of PKD2 cDNA,
corresponding to bp 2125 to 2973, designated XF-75, was subcloned into
the vector pBluescript II KS (Stratagene, La Jolla, CA) linearized by
EcoRV or NotI for anti-sense and sense probes,
respectively. The corresponding 850-bp riboprobes were synthesized as
detailed above using T7 and T3 RNA polymerase
(Boehringer-Mannheim) for the anti-sense and sense probes,
respectively. Six-µm-thick cryostat or paraffin-embedded sections
were produced. Before hybridization, the paraffin-embedded tissues were
pretreated by microwave heating in a sodium-citrate buffer (0.01 mol/L,
pH 6) to enhance the hybridization signal as previously
described.26
In situ hybridization was
performed according to a protocol previously reported.27
Immunohistochemistry
Antibodies and Western Blot Analysis
The rabbit anti-polycystin-1 serum against the cytoplasmic C-terminal tail of polycystin-1, has been generated using a fusion protein encoding the last 215 amino acids of the protein (amino acids 4088 to 4302) and described by Boletta and colleagues.12 Affinity purification of the antibodies was performed by immobilizing the immunizing antigen to resin, followed by affinity chromatography according to the manufacturer’s instructions (AminoLink Plus kit; Pierce, Rockford, IL). HEK cells were transiently transfected with the human full-length PKD1 cDNA. Transfected and untransfected cells were lysed in lysis buffer (250 mmol/L sucrose, 20 mmol/L imidazole, and 1 mmol/L ethylenediaminetetraacetic acid, pH 7.4, 0.5% Triton X-100) containing a protease inhibitor cocktail (Roche Molecular Biochemicals, Mannheim, Germany) by incubation at 4°C for 1 hour and centrifuged for 15 minutes at 14,000 rpm in a table microcentrifuge. The cleared total lysates were analyzed on Western blot similarly as described by Boletta and colleagues.12 Antibodies were diluted in 2% bovine serum albumin in Tris-buffered saline-T. The dilution for affinity-purified antibody was 1:200. It was 1:100 for the affinity-depleted serum and 1:1000 for the unpurified serum.
Two rabbit anti-polycystin-2 antibodies have been used. One was generated using the human sequence from amino acids 724 to 968. It was affinity purified and its specificity was confirmed by Western blot and immunoprecipitation of endogenous polycystin-2 from MDCK cells. The second anti-polycystin-2 antibody, YCC2, a gift from S. Somlo (Renal Division, Department of Internal Medicine, Yale School of Medicine, New Haven, CT), was generated against a fusion protein corresponding to amino acids 687to 962 of human polycystin-2. Membrane proteins from fetal (30 gestational weeks) and adult human kidneys were prepared as previously described.28 Western blot analysis using YCC2 polycystin-2 antibody (dilution, 1:4000) and the preabsorbed antisera as a negative control, was performed according to a protocol detailed by Cai and colleagues.28
The specificity and characterization of both polycystin-1 and polycystin-2 antibodies have already been detailed in a large number of reports12,16,20,28-30 . They have been used for immunohistochemistry and Western blot analysis and no signal was detected using the corresponding preimmune or depleted serum, on tissue sections or Western blot analysis.
Immunoperoxidase Staining
Immunostaining was performed on 6-µm-thick sections of paraffin-embedded or paraplast-embedded tissues using a standard immunoperoxidase protocol (Universal Immunostaining Streptavidin-Peroxidase Kit; Coulter-Immunotech, Marseille, France), after pretreatment by microwave heating in a 10 mmol/L citrate buffer, pH 6, as previously described.31 Antibodies to polycystin-1 were diluted to 1:500. Those to polycystin-2 were diluted to 1:50 to 1:100 for the first one and 1:200 for YCC2. The labeling patterns obtained with the two anti-polycystin-2 antibodies were similar. The staining with YCC2 was stronger thus the micrographs shown here were obtained using this antibody. Rabbit IgG (secondary antibody), preimmune sera, or antibodies preincubated with the corresponding polycystin-1 or polycystin-2 fusion protein were used as controls.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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The expression profile of PKD1 and PKD2
mRNAs was studied using multiple-tissue Northern blots. In adult
tissues, the highest expression of PKD1 was seen in heart
and brain; it was weaker in skeletal muscle and pancreas and very faint
in the kidney (Figure 1A)
. In fetal
tissues, PKD1 mRNAs were mainly expressed in brain and
kidney (Figure 1A)
. The weak level of the signal obtained by Northern
blot using Human Multiple Tissue Northern Blots (Clontech), may be
because of the large size of the transcripts. We also performed
Northern blot using RNA extracted from total fetal and adult kidneys
and the hybridization obtained with the same PKD1 probe was
consistently higher (data not shown). PKD1 transcript
expression has been studied in different tissues using RNase protection
assay.24
This assay has a higher sensitivity than Northern
blot and was used by these authors because of the size of the
PKD1 transcripts.
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. A lower band was also detected
in liver at 
3 kb. In fetal tissues, a strong expression was noted in
lung and kidney (Figure 1B)
. Western Blot Analysis
A polycystin-1 signal was difficult to detect in fetal and adult
kidney preparations with our antibody. This could be explained by
technical difficulties because of the size of the protein and the faint
level of expression in late stages of development, as was the case of
our tissue samples. However a band corresponding to the reported size
(520 kd) was easily detected in transfected cells and not seen when the
preimmune or the preabsorbed sera was used, nor was it seen in the
wild-type cells (Figure 2A)
. These
results are in accordance with previous reports.12,16
As
previously reported, the 110-kd signal was detected both in fetal and
adult kidneys after incubation with the polycystin-2 antibody but
abolished using antisera preabsorbed with the corresponding fusion
protein (Figure 2B)
.
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In situ hybridization and immunohistochemistry studies were performed on: 1) whole human embryo sections at 5 and 6 weeks of gestation; 2) fetal tissues (16 to 19 weeks); 3) fetal (10 to 38 weeks); and 4) postnatal (1 to 50 years) kidneys. In the human embryo three sets of kidneys differentiate successively from the intermediate mesoderm located on both sides of the body axis. The pronephros is a rudimentary and transitory structure that disappears after 4 weeks of embryonic development. The mesonephros begins to differentiate at 4 weeks, extends caudally along the mesonephric (or Wolffian) duct, is fully developed around the second month, and regresses at the end of the 4th month. The metanephros, the permanent kidney, begins to develop at 5 weeks when the ureteric bud, a diverticulum from the lower end of the Wolffian duct, reaches the caudal end of the nephric cord, or metanephric mesenchyma, and begins to branch. Differentiation of the first nephron units begins at 8 weeks and successive generations of nephrons develop up to 34 to 36 weeks of gestation, after the growth and branching of the ureteric bud. As such, mature and developing structures (vesicles, S-shaped bodies) co-exist during fetal life. The most mature nephrons are situated in the deep cortex, at the juxtamedullary junction whereas the immature structures are located in the superficial cortex.
Distribution of PKD1 mRNAs and Protein during Normal Kidney Development
In the 5- to 6-week embryos, PKD1 mRNAs were strongly
expressed in mesonephric tubules (Figure 3, A and B)
and absent in the primitive
metanephros consisting of the uninduced mesenchyma and the first
ureteric bud branches (Figure 3, C and D)
. At 10 weeks, a strong
hybridization signal had appeared in the first set of
differentiated proximal tubules (Figure 3
; E to H). No
significant signal was detected in the ureteric bud branches or the
blastema (mesenchyma). Between 10 to 24 weeks, the differentiated
proximal tubules continued to express high levels of PKD1
mRNAs. Thereafter the expression decreased progressively. At week 15,
discrete PKD1 expression was also seen in the distal part of
the nephrons and the ureteric bud branches (Figure 3, J and K)
. It
persisted at the same moderate level during fetal life. Hybridization
signals were no longer detected in mature kidneys. No signal was seen
in glomeruli, renal interstitium, or arteries of fetal or postnatal
kidneys. Results are summarized in Table 2
. No specific signal was detected with
the sense probes (Figure 3, I and L)
.
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, with a positive gradient of
expression with differentiation. No expression was detected in the
metanephros at that time. At 10 weeks, polycystin-1 labeling was
observed in proximal tubules. The expression increased rapidly with
maturation (Figure 4B)
, persisted at the same level to approximately
week 24, then declined progressively to persist at a very low level in
adult kidneys. Faint labeling of distal tubules and collecting ducts
was detected at 15 weeks. It persisted at a low level in collecting
ducts whereas it increased progressively with maturation in the
ascending limb of Henle loops and distal tubules (Figure 4C)
. The
labeling of the distal tubules and collecting ducts persisted in
adult kidneys (Figure 4D)
. No significant labeling
was detected in the blastema, early nephronic
structures, glomeruli, vessels, or interstitium. No signal was seen
with the preimmune serum or the serum absorbed with the polycystin-1
fusion protein (Figure 4, I and J)
.
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Strong expression of PKD2 transcripts was seen at
5 to 6 weeks in the mesonephros as well as in the uninduced metanephric
mesenchyma and the ureteric bud (Figure 5
; A to C). From 10 weeks, all developing
structures of the superficial cortex (condensates, vesicles, and
S-shaped bodies), as well as the ureteric bud branches, expressed
PKD2 transcripts (Figure 5, E and I)
. Expression by the
uninduced blastema was also present but weaker. In the underlying
parenchyma, all tubular segments expressed the PKD2
transcripts but the strongest expression was observed in distal tubules
and ascending limbs of Henle loops (Figure 5
; E, F, I, and J). Smooth
muscle cells of large intrarenal arteries (future interlobar and
arcuate arteries) showed clear positivity (Figure 5, G and K)
. Up to 36
weeks, the level of PKD2 expression remained high in the
differentiating structures of the outer cortex, in distal tubules,
cortical collecting ducts, and arterial vessels. In contrast,
PKD2 expression decreased rapidly and disappeared nearly
totally in proximal tubules as soon as they differentiated. In adult
kidneys, persistent expression was only observed in the ascending loop
of Henle, distal tubules, collecting ducts, and blood vessels (Figure 5, H and L)
. No expression was detected in the interstitium at any
stage of development. No expression was detected with the sense probe
(Figure 5D)
. Results are summarized in Table 2
.
|
. It was also seen, in contrast to what was observed for
polycystin-1, in the ureteric bud and the uninduced metanephric
blastema (Figure 6J)
. From 10 weeks,
labeling was observed in the ureteric bud branches and in the
developing nephrons from the vesicle stage (Figure 4F)
. The muscular
layer of large arteries was also strongly positive. During development
(10 to 38 weeks), expression of polycystin-2 progressively decreased in
proximal tubules, was low in the inner medulla portion of collecting
ducts, and persisted at a high level in ascending loop of Henle (Figure 4G)
, distal tubules, cortical collecting ducts, and large arteries. The
same distribution including the entire collecting system was seen in
mature kidneys (Figure 4H)
. No expression was noted in the
interstitium. No signal was observed with preimmune serum or after
competitive inhibition with the fusion protein (Figure 4, K and L)
.
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In the 5- to 6-week embryos, the expression of PKD1
mRNAs was moderate and diffuse, the hybridization signal being
prominent in the neural tube, especially in the anterior horn of the
spinal cord and in the neural ganglia (Figure 6, A and G)
. It was also
visible in the skin, the bronchial epithelia and the surrounding
mesenchyma, the digestive tract, the vertebral cartilaginous primordia,
the genital ridges, and the heart. At 16 weeks the neural expression
continues to be predominant (Figure 6I)
. No PKD1 transcripts
were detected in arterial walls. Polycystin-1 was mainly found in the
same neural embryonic structures and the cardiomyocytes (Figure 6D)
.
Labeling persisted at 16 weeks and was also observed in pancreas,
liver, adrenals, and testis.
PKD2 transcripts were diffusely expressed in a large variety
of tissues in the 5- to 6-week human embryo, especially in the neural
tube, the neural ganglia, the liver, and the heart (Figure 6B)
. At 16
weeks PKD2 expression was also seen in the aorta (Figure 6L)
. Polycystin-2 was found in the same structures (Figure 6E)
,
especially in neural tissue, with strong labeling of the anterior horn
of the spinal cord in the 6-week embryo (Figure 6J)
and in the 16-week
fetus (Figure 6K)
. With the sense probes a background signal was
observed in the liver whereas no significant signals were detected in
other tissues (Figure 6C)
. No labeling was observed with preimmune
serum, but a weak background was seen in the liver (Figure 6F)
.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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To overcome these difficulties, probably partly because of differences in antibody specificity, we analyzed by in situ hybridization the expression of both transcripts during embryogenesis and in renal development. This approach has not been reported previously in humans. In parallel, we analyzed by immunohistochemistry the distribution of polycystin-1 and polycystin-2, in an attempt to correlate proteins and transcripts distribution. For each gene, the expression pattern of transcripts and protein was concordant.
During human development, both transcripts are widely expressed at 5 weeks of gestation, the earliest stage studied. The expression was seen in cardiomyocytes, endodermal derivatives, and liver. It was prominent in neural tissue, especially the anterior horn of the spinal cord and the neural ganglia. This distribution persists in the 16-to 19-week fetuses, the latest stage examined. As expected from the pattern of expression, cardiac involvement, hepatic cysts, and colonic diverticulae may be observed in ADPKD patients. However, neurological symptoms are consistently absent in ADPKD patients despite the early and strong expression of both genes in neural tissue. This is not an unusual situation. Indeed, dissociation between a widespread gene expression and restricted clinical phenotype has been observed for example in nephronophthisis,42 another hereditary renal disease. The arterial expression of the genes was carefully screened as one severe manifestation of both forms of ADPKD is the development of intracranial aneurysms.43 An early and strong expression of PKD2 transcripts and protein was found in large renal and extrarenal arteries, including the aorta of a 16-week fetus, and persisted at the same level in adult renal arteries. This confirms previous immunohistochemical studies.28,30,40,44 Vascular expression of Pkd1 transcripts has also been observed in mice,45,46 and one model of Pkd1 knockout mice exhibits rupture of blood vessels leading to embryonic lethality.47 However, no arterial PKD1 transcripts or protein could be detected in our study.
In human 5- to 6-week embryos, PKD1 and PKD2 are co-expressed in mesonephric tubules whereas PKD2 only is expressed in the metanephros. Later on, PKD2 continues to be widely expressed in the metanephros, at all stages of nephron development and in all segments of differentiated tubules. In contrast, PKD1 transcripts and protein are absent in the blastema and the immature nephrons whereas they abruptly arise in differentiated proximal tubules of the first row of developed nephrons. Findings are different in mice that show Pkd1 expression throughout the condensing metanephric mesenchyme, a distribution suggesting a role of polycystin-1 in the early processes of condensation and transdifferentiation,45 a hypothesis not supported by our observations. Moreover, the initial and intense expression of PKD1 in proximal tubules is in agreement with the development of lesions in Pkd1 knockout mice: in the latter, nephrogenesis occurs normally and first cystic dilations develop secondarily from proximal tubules.48 The expression of both genes in proximal tubules decreases progressively during fetal life to become practically undetectable in postnatal kidneys. PKD1 transcripts, secondarily seen in distal tubules and collecting ducts, are no longer detected in adult kidneys that maintain a faint expression of polycystin-1. In contrast, persistent expression of PKD2 transcripts and protein is observed. Generally, contrary to previous observations at the protein level in humans,40 and at the RNA level in mice,46,47 we found differences in the spatiotemporal expression of PKD1 and PKD2 during nephrogenesis, PKD2 being expressed earlier and more diffusely than PKD1. Differences in the developmental expression of polycystin-1 and polycystin-2 were also observed by Foggensteiner and colleagues.41 These data suggest that polycystins could interact with different partners at least during kidney development.
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Acknowledgements |
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Footnotes |
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Supported by the Institut National de la Santé et de la Recherche Scientifique, the Association Claude Bernard, the Fondation pour la Recherche Médicale, the Association pour l’Utilisation du Rein Artificiel and the Assistance Publique des Hôpitaux de Paris, the Belgian agencies FNRS and FRSM, the Fondation Alphonse et Jean Forton, the Association pour l’Information et la Recherche sur les Maladies Rénales Génétiques, and a grant from the Fondation pour la Recherche Médicale, the INSERM, and a bilateral grant from the CGRI and INSERM (to V. C.).
Part of this work was presented in abstract form at the 32nd American Society of Nephrology meeting, Miami, October 1999.
Accepted for publication December 7, 2001.
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References |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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-dependent and c-Jun N-terminal kinase-dependent activation of the transcription factor AP-1. J Biol Chem 1998, 273:6013-6018This article has been cited by other articles:
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  J. A. Driscoll, S. Bhalla, H. Liapis, A. Ibricevic, and S. L. Brody Autosomal Dominant Polycystic Kidney Disease Is Associated With an Increased Prevalence of Radiographic Bronchiectasis Chest, May 1, 2008; 133(5): 1181 - 1188. [Abstract] [Full Text] [PDF]
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 R. Rohatgi, L. Battini, P. Kim, S. Israeli, P. D. Wilson, G. L. Gusella, and L. M. Satlin Mechanoregulation of intracellular Ca2+ in human autosomal recessive polycystic kidney disease cyst-lining renal epithelial cells Am J Physiol Renal Physiol, April 1, 2008; 294(4): F890 - F899. [Abstract] [Full Text] [PDF]
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M. Murakami, T. Ohba, F. Xu, S. Shida, E. Satoh, K. Ono, I. Miyoshi, H. Watanabe, H. Ito, and T. Iijima Genomic Organization and Functional Analysis of Murine PKD2L1 J. Biol. Chem., February 18, 2005; 280(7): 5626 - 5635. [Abstract] [Full Text] [PDF]
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