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2 Deposition Is Species Independent
*
Department of Pediatrics, University of Minnesota Medical School,
Minneapolis, Minnesota
Texas Veterinary Medical Center, Texas A&M University, College
Station, Texas
Division of Pathology, Hospital for Sick Children and University of
Toronto, Toronto, Canada
§
Department of Anatomy, University of Helsinki, Institute of Biomedicine,
Helsinki, Finland
||
Department of Medicine, Washington University School of Medicine, St.
Louis, Missouri.
Correspondence to Dr. Clifford E. Kashtan, Department of Pediatrics, University of Minnesota Medical School, Box 491, UMHC, 515 Delaware Street, SE, Minneapolis, MN 55455. Phone: 612-624-9193; Fax: 612-626-2791; E-mail: kasht001{at}tc.umn.edu
 |
Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, ß, and 
chains using monospecific antibodies. Laminin 2 chain was absent from
glomerular basement membranes (GBM) in normal human, murine, and canine
kidneys but was abnormally deposited in Alport GBM, regardless of species or
inheritance pattern. In murine and canine Alport kidneys, laminin 2
seems to be deposited as part of both laminin-2 (2ß11) and
laminin-4 (2ß21) but as part of only laminin-4 in human
Alport kidneys. GBM laminin 2 chain deposition was not observed in a
variety of non-Alport human glomerulopathies. This finding adds to the list of
proteins that are aberrantly deposited in Alport GBM as a consequence of the
absence of the 3, 4, and 5 chains of type IV collagen:
(1) type IV collagen 1 and 2 chains, (2) type
V collagen, (3) type VI collagen, and most recently (4) the
laminin 2 chain and (5) the laminin 1 and ß1
chains in mice and dogs. These findings emphasize further the critical role
played by the 3, 4, and 5 chains of type IV collagen in
establishing and maintaining the composition, structure, and function of
mature GBM. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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3(IV), 4(IV), or
5(IV) chains, are associated with loss of these chains from GBM and
their replacement by 1(IV) and 2(IV) chains. This compensatory
substitution allows normal glomerulogenesis to take place and supports normal
glomerular filtration and permselectivity early in life but results ultimately
in renal failure. Identical abnormalities in glomerular expression of type IV
collagen have been described in various forms of Alport syndrome: human
X-linked Alport syndrome (XLAS) caused by mutations in COL4A5, the gene
encoding the 5(IV) chain
(2,3);
human autosomal-recessive Alport syndrome (ARAS) caused by mutations in COL4A3
and COL4A4, which encode the 3(IV) and 4(IV) chains,
respectively (4); spontaneous
XLAS and ARAS in dogs
(5,6,7);
and ARAS in knockout mice with Col4a3 mutations
(8,9,10).
Besides type IV collagen, the other major glycoprotein constituents of
mature GBM are laminin, nidogen, and the proteoglycan agrin
(11). Laminin molecules are
trimers composed of an , ß, and chain
(11). At least 11 distinct
laminin chains have been described (five , three ß, and three
chains), which can combine into at least 12 different laminin trimers
(laminins 1 through 12). The predominant laminin trimer of mature GBM is
laminin-11 (5ß21)
(12). The mesangium of mature
glomeruli contains laminin-1 (1ß11) and laminin-2
(2ß11)
(12). Studies of laminin
expression in Alport glomeruli have yielded mixed results. Studies of human
and canine Alport syndrome reported no overt changes in GBM laminin
expression, but the antibodies used in these studies were able to identify
only a limited set of laminin chains
(13,14).
Analyses of glomerular expression of laminin ß1, ß2, and 1
chains in murine ARAS and canine XLAS and ARAS similarly failed to identify
significant changes, other than the appearance of laminin ß1 in GBM of
sclerosing glomeruli in murine ARAS
(6,7,8,9).
There is no evidence that Alport syndrome can be caused by mutations at
loci encoding laminin chains, and although laminin ß2 knockout mice
develop nephrotic syndrome, they have no features of Alport syndrome
(15). Thus, one would not
expect to find that laminin-11 disappears from Alport GBM. However, it is
possible that the change in the GBM type IV collagen phenotype modifies
laminin expression in Alport GBM, perhaps by stimulating the expression of
laminin chains that are typically found in association with the 1 and
2 chains of type IV collagen. One might also expect that any changes in
GBM laminin expression induced by the altered type IV collagen phenotype would
be common to various forms of Alport syndrome in various species, because this
change in GBM type IV collagen is a constant feature of the disease,
regardless of inheritance or species. Therefore, we performed a survey of
renal laminin expression in murine, canine, and human forms of XLAS and ARAS,
using antibodies specifically targeting laminin 1, 2, 5,
ß1, ß2, and 1.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1 or 5 known to
us.
|
Tissues
Human Alport Syndrome. Renal biopsy or nephrectomy specimens from
six males with XLAS (ages 9 to 13 yr) and one female with ARAS (age 7 yr) were
obtained in the course of clinical evaluation of hematuria or in preparation
for renal transplantation. Renal function at the time that tissue was obtained
ranged from normal to end-stage renal failure. All renal specimens exhibited
characteristic ultrastructural changes in GBM by electron microscopy
(22). All six specimens from
males with XLAS displayed absence of reactivity with monoclonal antibodies
against the 3, 4, and 5 chains of type IV collagen and
abnormally increased GBM reactivity with mono-specific antibodies against the
1(IV) and 2(IV) chains, a pattern that is diagnostic of XLAS
(23). The specimen from the
female with ARAS displayed absence of reactivity with monoclonal antibodies
against the 3(IV) and 4(IV) chains; antibody against the
5(IV) chain did not stain GBM in this specimen but did stain Bowman's
capsules and distal tubular basement membranes (TBM). This pattern is
characteristic of ARAS (4).
This specimen also exhibited increased GBM staining for the 1(IV) and
2(IV) chains.
Normal human kidneys specimens (n = 9) from subjects 8 d to 60 yr of age were also examined for laminin chain expression. Control disease kidney specimens were available from patients with diabetic nephropathy (n = 12), membranoproliferative glomerulonephritis type I (n = 6), membranous nephropathy (n = 4), minimal change nephrotic syndrome (n = 5), focal segmental glomerulosclerosis (n = 2), and IgA nephropathy (n = 8).
Canine Alport Syndrome. Renal biopsy specimens were available from
mixed-breed (Navasota) and Samoyed dogs with XLAS
(5,6)
and from English Cocker Spaniels (ECS) with ARAS
(7). All dogs examined were
male. These dogs exhibit hematuria, proteinuria, and progressive renal
insufficiency, and ultrastructural GBM changes pathognomonic of Alport
syndrome. In male dogs with XLAS, renal tissues show no staining for the
3(IV), 4(IV), and 5(IV) chains, whereas GBM staining for
1(IV) and 2(IV) chains is increased, as in human XLAS
(6). In ECS dogs of either
gender with ARAS, renal tissues show no staining for the 3(IV) and
4(IV) chains, whereas the 5(IV) chain is weakly expressed in
GBM, with strong expression in Bowman's capsules and distal TBM, similar to
human ARAS (7). The GBM of
affected ECS dogs also exhibits increased expression of 1(IV) and
2(IV) chains.
The Navasota and ECS dogs were 6 to 12 mo of age at the time that their kidneys were sampled, and all had renal insufficiency, proteinuria, and extensive ultrastructural changes in GBM. The Samoyed dog was 1.5 mo of age, with no clinical renal disease but some lamellation of GBM by electron microscopy.
Murine Alport Syndrome. This model of ARAS results from a partial
deletion of Col4a3 introduced by homologous recombination
(8). Homozygous mutant mice
develop proteinuria and renal insufficiency, associated with pathognomonic
ultrastructural changes in GBM. Staining of GBM for 3(IV),
4(IV), and 5(IV) chains is negative, whereas GBM staining for
1(IV) and 2(IV) chains is markedly increased
(8). Kidneys examined in the
present study were obtained from 44- to 46-d-old mice. ARAS mice of this age
have normal serum creatinine, blood urea nitrogen, and urinary protein levels
and no obvious renal lesions by light microscopy. Electron microscopy shows
focal GBM lamellation at this age.
Immunofluorescence Microscopy
Tissues were embedded in Tissue-Tek OCT (Miles, Elkhart, IN) and
snap-frozen in liquid nitrogen. Tissue sections were fixed for 10 min in
acetone. After the slides were washed in fresh buffer (0.01 M
phosphate-buffered saline, pH 7.4), they were incubated in a moist chamber
with the appropriate dilution of primary antibodies. Incubation with FITC or
Cy3 secondary antibodies was then performed. A mounting media containing
p-phenylenediamine was used to retard fluorescence quenching.
Labeling was examined with an epifluorescence microscope with appropriate
filters (Carl Zeiss, Inc., Oberkochen, Germany, or Nikon, Melville, NY).
Tissue sections directly incubated with secondary antibodies served as
controls, and negative results were obtained in all instances.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1 chain showed reactivity with mouse or human kidneys but
not with dog kidney. In human kidney, the laminin 1 chain was present
in some TBM but was absent from glomeruli
(Figure 1). In mouse kidneys,
laminin 1 chain was present in the mesangium and in some TBM
(Figure 2). Antibody against
laminin 2 chain showed weak, focal mesangial staining, as well as
staining of blood vessels in human and dog kidney (Figures
3 and
5). In the mouse, 2 was
detected in mesangium and weakly in some TBM segments
(Figure 4). The laminin
5 chain was present in all basement membranes in human and mouse
kidneys, but neither antibody against this chain (4C7 or the polyclonal
anti-murine laminin 5) reacted with dog kidney. Antibody to laminin
ß1 stained all TBM and Bowman's capsules and exhibited weak staining of
the mesangium, in humans, dogs, and mice (Figures
4 and
6). The laminin ß2 chain
was observed in GBM, Bowman's capsules, and vascular basement membranes in all
three species, and there was weak staining of some TBM in human kidney.
Staining for the laminin 1 chain was widespread in human, canine, and
murine kidneys, with reactivity in mesangium, GBM, Bowman's capsules, blood
vessels, and TBM (Figure
4).
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Alport Tissues
Laminin 1 Chain. As in normal human kidneys, human Alport
kidneys showed staining of some TBM for the laminin 1 chain, but no
glomerular staining was observed (Table
2, Figure 1). In
contrast, murine Alport kidneys showed focal GBM staining for the laminin
1 chain (Figure 2).
Laminin 2 Chain. All Alport kidneys exhibited enhanced
glomerular expression of the laminin 2 chain. The degree of enhancement
varied among the kidneys, as did the distribution of laminin 2 chain
expression. In humans, GBM expression of laminin 2 chain was diffuse
and strong in some Alport kidneys but more segmental in other kidneys
(Figure 3). None of the
non-Alport diseased kidneys exhibited laminin 2 chain expression in GBM
(data not shown).
Kidneys from Alport mice at a relatively early stage of the disease showed
similar diffuse, segmental staining in the GBM, and 2 staining was
especially prominent in thickened capillary loops
(Figure 4). In canine forms of
Alport syndrome, although GBM staining for the laminin 2 chain was not
as strong as in human and murine disease, a marked difference between normal
dogs and Alport dogs in GBM staining for the laminin 2 chain was
apparent (Figure 5).
Laminin 5 Chain. Kidneys from humans and mice with Alport
syndrome revealed strong staining of all basement membranes for the laminin
5 chain, regardless of inheritance pattern. As in normal dog kidneys,
kidneys from dogs with Alport syndrome showed no reactivity with the 4C7
anti-laminin 5 chain antibody.
Laminin ß1 Chain. TBM and Bowman's capsules in all Alport
kidneys stained strongly for the laminin ß1 chain, with weak mesangial
reactivity. Some glomeruli in murine Alport kidneys showed segmental GBM
staining for the laminin ß1 chain, and this could be co-localized in many
cases with the 2 chain (Figure
4). Similarly, segmental GBM staining for laminin ß1 was
present in canine Alport kidneys (Figure
6). Human Alport kidneys showed only weak mesangial staining for
laminin ß1 (Figure 7).
|
Laminin ß2 Chain. Antibody to the laminin ß2 chain exhibited intense staining of GBM, Bowman's capsules, and vascular basement membranes in all Alport kidneys.
Laminin 1 Chain. The laminin 1 chain was strongly
expressed in mesangium, GBM, Bowman's capsules, and TBM. In mice, thickened
segments of GBM stained strongly with the anti-1 antibody, and this
could be co-localized with 2 deposition
(Figure 4).
Thus, laminin 2 was aberrantly deposited in all Alport GBM in a
species-independent manner. Species-dependent deposition in Alport GBM was
observed for laminin 1 in mice and for laminin ß1 in mice and
dogs. In Alport mice, the deposition of these chains was most apparent in
thickened GBM segments. The expression patterns and intensity of staining for
the laminin 5, ß2, and 1 chains in Alport kidneys were
similar to the patterns and intensities of staining for these chains in normal
kidneys.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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3(IV), 4(IV), and 5(IV)
chains. Young Alport subjects exhibit little or no lamellation of GBM and do
not exhibit proteinuria, despite the absence of the 3(IV),
4(IV), and 5(IV) chains from GBM. This suggests that other
alterations in the composition of Alport GBM contribute to the structural and
functional GBM abnormalities that appear as Alport subjects age.
Some of these alterations in GBM composition have been identified. In the
normal developing kidney, 1(IV) and 2(IV) chains predominate in
the primordial GBM of immature glomeruli
(3,5,27).
The formation of capillary loops within the maturing glomeruli is associated
with the appearance of 3, 4, and 5(IV) chains in the GBM.
As glomerular maturation progresses, the 3, 4, and 5(IV)
chains become the predominant type IV collagen chains in GBM. This process,
referred to as "isotype switching," does not take place in Alport
subjects
(3,5,8,9).
Instead, the 1(IV) and 2(IV) chains remain the predominant
collagenous constituents of the Alport GBM. Whereas in normal mature GBM the
1(IV) and 2(IV) chains are confined to the subendothelial region
of the GBM, these chains spread throughout the width of the GBM in Alport
kidneys
(2,28).
The intensity of GBM staining for these chains increases with increasing
duration of disease, although the 1(IV) and 2(IV) chains
disappear from end-stage, obsolescent Alport glomeruli
(2).
In human Alport syndrome, type V collagen and type VI collagen also
accumulate abnormally in GBM. These collagens are normally expressed in the
mesangium and in the subendothelial region of the GBM
(2). Alport kidneys exhibit a
progressive increase in the intensity of GBM staining for types V and VI
collagen, and these collagens spread from their normal subendothelial location
to occupy the entire width of the GBM
(2). Unlike the 1(IV)
and 2(IV) chains, types V and VI collagen persist in the GBM of
end-stage Alport glomeruli.
Previous studies of laminin expression in the GBM of human and canine subjects with Alport syndrome did not reveal specific abnormalities (13,14). However, at the time that these studies were performed, little was known about the tissue-specific expression of laminin isoforms and the available probes were broadly reactive. Habib et al. (13) reported that staining of Alport GBM for laminin was positive in 11 of 11 patients. The immunogen used to generate the antiserum was not specified, but it is likely that the antiserum contained antibodies against several laminin isoforms. Thorner et al. (14) examined laminin expression in GBM of dogs with Samoyed hereditary glomerulopathy, an X-linked form of Alport syndrome. No differences between normal and affected dogs in laminin expression were observed. The antiserum used stained all basement membranes as well as mesangium in normal kidneys, suggesting that the antiserum contained antibodies against multiple laminin isoforms.
More recent studies of laminin expression in kidneys of animals with Alport
syndrome used monospecific antibodies against laminin ß1, ß2, and
1 chains. GBM of dogs with X-linked or autosomal-recessive Alport
syndrome stained positively for laminin ß2 and 1 chains but not
for the laminin ß1 chain
(6,7).
In knockout mice with autosomal-recessive Alport syndrome, staining of GBM for
laminin ß2 and 1 chains was positive
(8,9).
In addition, GBM of mice with advanced disease showed weakly positive staining
for the laminin ß1 chain.
The notable finding of the present study is that ectopic deposition of the
laminin 2 chain in GBM is common to humans, dogs, and mice with
X-linked or autosomal-recessive forms of Alport syndrome. We did not observe
laminin 2 chain deposition in GBM of renal specimens from patients with
a variety of other glomerulopathies, indicating that GBM deposition of the
laminin 2 chain in GBM is unique to Alport syndrome. We did not attempt
to correlate GBM laminin 2 chain deposition with subject age, degree of
renal functional impairment, or extent of structural changes by light or
electron microscopy in human and canine subjects. However, GBM laminin
2 chain deposition was observed in Alport males with normal creatinine
clearance as well as those with end-stage renal failure, suggesting that this
anomaly is not simply a manifestation of advanced disease. In knockout mice,
laminin 2 deposition in the GBM was observed segmentally at a stage
before proteinuria and reduced glomerular filtration was apparent. In canine
Alport syndrome, deposition of laminin 2 chain in GBM was observed in
dogs with normal renal function and no proteinuria, as well as in dogs with
advanced renal insufficiency and substantial proteinuria. These observations
suggest that laminin 2 deposition is not secondary to defects in renal
function but may be a consequence of phenotypic changes in the cells abutting
the mutant GBM.
The laminin 2 chain participates in two known laminin trimers:
laminin-2 (2ß11) and laminin-4 (2ß21).
Because the GBM expression of the laminin 2 chain in human Alport
kidneys was not matched by a similar anomaly of laminin ß1 expression, we
believe that the laminin 2 chain is incorporated into the human Alport
GBM as a component of laminin-4 trimers. However, in the GBM of Alport mice,
both laminin-2 and laminin-4 likely are present, as we could co-localize the
2 and ß1 chains. Laminin ß1 was also present in some segments
of GBM in dogs with Alport syndrome, suggesting the presence of both laminin-2
and laminin-4. Extraction of laminin trimers from Alport GBM and analysis of
their composition would be required to prove that the laminin 2 chains
are involved in laminin-2 or laminin-4 trimers. The discrepancy between human
Alport syndrome, as opposed to murine and canine Alport syndrome, in GBM
laminin ß1 deposition may reflect species-specific differences in the
regulation of the expression of this protein.
Focal GBM staining for the laminin 1 chain, probably as part of the
laminin-1 trimer, was observed in mouse Alport kidneys but not in human Alport
kidneys. The reason for this difference is unknown but may reflect
species-specific differences in laminin gene expression, given that laminin
1 chain is expressed in the mesangium of normal murine kidneys but not
in normal human kidneys. It is not clear whether GBM deposition of the laminin
2 chain has significant structural or functional consequences. However,
this finding adds to the list of proteins that are uniquely overexpressed in
Alport GBM as a consequence of the absence of the 3, 4, and
5 chains of type IV collagen: (1) type IV collagen 1
and 2 chains, (2) type V collagen, (3) type VI
collagen, and most recently (4) the laminin 2 chain and
(5) the laminin 1 and ß1 chains in mice and dogs. These
findings emphasize further the critical role played by the 3, 4,
and 5 chains of type IV collagen in establishing and maintaining the
composition, structure, and function of mature GBM.
|
Acknowledgments |
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Footnotes |
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Cosgrove and colleagues recently described GBM laminin 2 expression
in a murine different model of autosomal-recessive Alport syndrome (Cosgrove
D, Rodgers K, Meehan D, Miller C, Bovard K, Gilroy A, Gardner H, Kotelianski
V, Gotwals P, Amatucci A, Kalluri R: Integrin 1ß1 and transforming
growth factor-ß1 play distinct roles in Alport glomerular pathogenesis
and serve as dual targets for metabolic therapy. Am J Pathol 157:
1649-1659, 2000).
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1 and 2 chains
of collagen IV and of collagens V and VI in Alport syndrome. Kidney
Int 42: 115-126,1992[Medline]
3(IV): Implications for Alport syndrome.
J Cell Biol 135:1403
-1413, 1996 chains: expression, developmental
transitions, and chromosomal locations of 1-5, identification of
heterotrimeric laminins 8-11, and cloning of a novel 3 isoform.
J Cell Biol 137:685
-701, 19971-chain shows a restricted
distribution in epithelial basement membranes of fetal and adult human
tissues. Exp Cell Res 257:298
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3, 4 and 5
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: 879-891,19945 chain and lack of laminin 1
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J Biol Chem 272:28590
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