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1 Department of Medicine, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115; and 2 Division of Nephrology, Children's Hospital and Regional Medical Center, University of Washington School of Medicine, Seattle, Washington 98105
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
INTEGRIN EXPRESSION DURING...
INTEGRIN EXPRESSION IN ADULT...
REFERENCES
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Integrins are heterodimeric cell surface receptors that mediate heterophilic cell-cell interactions and interactions between cells and the extracellular matrix (Hynes RO. Cell 69: 11-25, 1991). As such, they are involved in morphogenetic processes during development, as well as in the maintenance of normal tissue architecture in fully developed organs. Integrins are now recognized to be a large family of receptors, and several different integrins have been demonstrated as being expressed in the developing and adult kidney (Korhonen M, Ylkanne J, Laitinen L, and Virtanen I. Development 122: 3537-3547, 1996; Rahilly MA and Fleming S. J Pathol 167: 327-334, 1992). This review will summarize present knowledge about integrin expression in the developing, normal, and diseased kidney and attempt to provide a hypothetical framework for understanding integrin function in the urogenital system. Since the last time this area was reviewed (Hamerski DA and Santoro S. Curr Opin Nephrol Hypertens 8: 9-14, 1999), there have been significant publications on the roles of integrins in kidney development and disease. At present, there are many more questions than answers, and integrins present an area where many novel and exciting findings will emerge in the coming years.
adhesion receptors; nephrogenesis; kidney disease
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
INTEGRIN EXPRESSION DURING...
INTEGRIN EXPRESSION IN ADULT...
REFERENCES
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IN
MAMMALS, more than 20 integrin heterodimers are expressed, each
of which is comprised of a single 
- and 
-subunit. In most
cases, more than one type of -subunit is found to heterodimerize with a particular -subunit; thus integrins are usually divided into
subgroups on the basis of the -subunit. The group of integrins demonstrating the most widespread expression in the kidney are those
that contain the 1-subunit; this is the subgroup of
integrins that serves as the major family of receptors for the
extracellular matrix (ECM) in mammalian tissues. The
1-integrins have been characterized as receptors for
fibronectin, collagen, vitronectin, thrombospondin, and distinct
isoforms of laminin. (The specificity of each integrin is denoted in
the text.) Integrin function in tissues is inferred from in
vitro studies demonstrating binding to different components of the ECM.
For example, those expressed by mesenchymal cells that bind connective
tissue components such as type I collagen or fibronectin are believed
to act by anchoring mesenchymal cells within the surrounding ECM.
Alternatively, integrins expressed on the basal surface of epithelial
cells, which mainly bind laminin, are presumed to adhere cells to their
laminin-rich basement membranes. This review will focus on the role of
integrins themselves. A recent review in this journal has focused more
generally on the role of the extracellular matrix and its receptors in
the kidney (62).
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INTEGRIN EXPRESSION DURING KIDNEY DEVELOPMENT |
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ABSTRACT
INTRODUCTION
INTEGRIN EXPRESSION DURING...
INTEGRIN EXPRESSION IN ADULT...
REFERENCES
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A small number of studies have characterized integrin expression in the developing kidney (31, 47). Nearly all of these studies have utilized human fetal kidneys and have examined integrin expression in the nephrogenic zone of the developing cortex. Thus these studies do not encompass the initial period of metanephric induction and early branching morphogenesis, presumably because of the difficulty of obtaining human fetal tissue from these early time points. Furthermore, complete studies of integrin expression have not been performed in rodents, where such early embryos can easily be obtained. Therefore, although we have a good understanding of integrin expression during the differentiation of the nephron, it is also possible that distinct integrin-mediated interactions occur during early kidney development, a point to be addressed later in this review. This point is important because morphological studies on the development of kidney architecture have demonstrated a distinction between the early rounds of branching morphogenesis that contribute to the major and minor calyces and medullary papillae and subsequent dichotomous branching events that give rise to medullary-cortical collecting ducts (41, 42).
Expression and Function During Metanephric Induction
The development of the nephron within the nephrogenic zone of the cortex involves an initial condensation of renal stem cells around a derivative of the ureteric bud (4, 56). Continued branching of the ureteric bud gives rise to the collecting ducts. Branching of the derivatives of the ureteric bud is initially symmetrical, after which a dichotomous branching pattern gives rise to the complex architecture of the collecting system. The condensed stem cells form pretubular aggregates that then undergo a mesenchymal-to-epithelial transformation, leading to the formation of a simple epithelial tubule. The tubule then undergoes a complex pattern of differentiation, involving elongation, segmentation, and convolution to finally form a mature nephron. As each nephron matures, a connection is established between the end of the nascent distal tubule and a portion of a ureteric bud derivative that is itself maturing into a collecting duct. These stem cells also give rise to the stromal population present during nephrogenesis and thereafter (4). Rahilly and Fleming (47) detected expression of41-integrin, a receptor for
fibronectin and vascular cell adhesion molecule, by undifferentiated
cells along the periphery of the kidney. This population presumably
included but was not restricted to renal stem cells. However,
expression of 41 in this region was not
confirmed by Korhonen et al. (31) in their study of
integrin expression during kidney development. Korhonen et al. and
Rahilly and Fleming (47) also examined ureteric bud derivatives and maturing nephrons of the nephrogenic zone of human fetal kidneys for expression of different -integrin subunits. Ureteric bud derivatives along the periphery of the cortex expressed abundant 61- and smaller amounts of
31-integrin. The
61- and
31-integrins were also expressed in the
part of the pretubular aggregate that had undergone epithelialization,
with 31 mainly restricted to that part of
the nascent tubule containing presumptive glomerular podocytes (also
referred to as visceral epithelial cells) (31,
47). Other than the diffuse expression of
41-integrin detected by Rahilly and
Fleming (47), neither the stem cell population lining the
periphery of the kidney nor the areas where stem cells condensed around
the ureteric bud during pretubular aggregate formation demonstrated
specific integrin expression before that of
31 and 61
noted above. However, it is possible that future studies will
demonstrate integrin expression in this cell population.
One of the most striking roles for integrins in kidney development was
revealed on targeting the 8-integrin gene in mice (37). The 81-integrin is
expressed on the metanephric mesenchyme at sites where it is in contact
with the ureteric bud (37). In most 8-null
embryos, extension of the ureteric bud ceases on contact with the
metanephric mesenchyme, and no kidney is produced. For unknown reasons,
in a fraction of null embryos kidney development progresses to varying
extents and small kidneys are formed that in rare instances can
actually maintain postnatal viability of null mice. The key ligand of
81 in the kidney is not known with certainty. The 81-integrin appears to be
a receptor for fibronectin and osteopontin and probably for other as
yet unidentified ligands (13, 37).
Fibronectin-deficient embryos die before the onset of kidney
development (18), but it is unlikely that a molecule with
such widespread expression would also act as the exclusive ligand in a
specific interaction between the ureteric bud and the metanephric
mesenchyme. Additionally, because kidney development is normal in the
osteopontin-mutant mouse (49), it is unlikely that
osteopontin is the only relevant ligand. However, in experiments where
anti-osteopontin antibodies were added to metanephric organ cultures,
some inhibition of growth was observed (50). This provides
one of several known examples where the results of genetic knockout and
antibody inhibition experiments are not in agreement and leave open the
possibility that interactions between
81-integrin and osteopontin are crucial
during kidney development
The knowledge that normal nephrogenesis requires an interaction between
81-integrin and an unknown ligand adds to
the number of ligand-receptor events previously demonstrated to be
crucial for early kidney development. These include interactions among c-ret and glial-derived neurotropic factor (GDNF)/GDNF receptor-, Wnt-4, and a presumed Frizzled receptor, and between BMP-7 and its
receptor (reviewed in Ref. 34). Indeed, given the growing awareness
that signals transduced by integrin-ECM interactions and growth
factor-receptor interactions are often integrated within cells to
produce physiological responses, it will be of great interest to
eventually determine whether a growth factor such as GDNF signals
coordinately with 81-integrin.
Expression During Nephron Differentiation
Thus far, only expression of1-integrins has been
examined in detail during the development of individual nephrons. It is very likely that additional integrins are expressed in the developing kidney, particularly v3 and/or
v5 in the developing vasculature. Whether
these integrins might have functions unique to the kidney that are not
observed during vasculogenesis and angiogenesis in other organs remains
to be determined.
11.
The 11-integrin, which is a receptor for
collagen and laminin, was found to be expressed in S-shaped tubules
mainly by cells invading the glomerular cleft, i.e., those cells that
will contribute to the capillary network within the glomerulus. In more
mature glomeruli, 11 continued to be
restricted to the mesangial area within glomeruli (31,
47).
21.
The 21-integrin, a receptor for laminin
and collagen, is expressed in the part of the S-shaped tubule that will
contribute to proximal but not distal tubules (31,
47). Expression is also observed in endothelial cells
within capillary loops of immature glomeruli (31,
47). In more mature kidneys,
21-integrin is expressed by distal
tubules and collecting ducts, as well as glomerular endothelial cells
(31, 47).
31.
The 31-integrin was originally
characterized as a promiscuous receptor, binding collagen, fibronectin,
laminin, and entactin/nidogen (11, 14,
45, 64). More recent studies have
demonstrated that although ECM components might be weak ligands,
31 binds with much higher affinity to
isoforms of laminin, including laminin-5 and laminin-10/11
(12, 30). Because little if any laminin-5 is
present in the kidney, it is likely that either laminin-10 or -11, which contains the 5 chain as part of the laminin
heterotrimer, is the important ligand for this integrin in the kidney.
Indeed, 5-containing laminins are colocalized with sites
of 31-integrin expression within the
kidney (63). As mentioned above,
31 is expressed weakly by the ureteric
bud and most highly in those cells of the early tubule that represent
the presumptive podocytes (31, 47). Weaker
staining is also seen in the cells of the forming Bowman's capsule.
Proximal and distal tubule precursor cells do not express
31, although in more mature kidneys
expression is observed in distal tubules and collecting ducts
(31, 47). In maturing glomeruli,
31 is highly expressed by glomerular podocytes in a polarized pattern along the glomerular basement membrane
(GBM) (31, 47).
3-integrin gene have several defects in kidney
development (32). As discussed above,
31 is the predominant integrin expressed
along the basal surface of podocytes. Podocytes deficient in
31-integrin appear unable to assemble
mature foot processes, and, instead, cytoplasmic projections from the
podocyte cell body are flattened against the GBM (32).
Moreover, the GBM itself is fragmented, and along much of its length
there appears to be a failure of fusion of the epithelial- and
endothelial-derived components. Additionally, there appear to
be fewer capillary loops in each glomerulus, and individual loops have
a much wider diameter than usual, such that several blood cells are
observed in histological sections through capillaries within glomeruli
(32). This histological picture suggests a dynamic process
during glomerulogenesis, where migration of podocytes around ingrowing
capillaries, mediated by 31-integrin, plays an essential role in stimulating capillary branching and maturation of the basement membrane.
The lack of formation of mature foot processes in
31-integrin-deficient podocytes suggests
that signals transduced by this integrin are essential for triggering
the cytoskeletal rearrangements required to assemble and maintain foot
process structure (see Fig. 1). Because
31-deficient podocytes appear to remain
adherent to the basement membrane along their entire length of contact, rather than simply dissociating from the basement membrane altogether, it seems the concept of integrins as simple adhesion receptors is
oversimplified. Instead, it may be more appropriate to think of
integrins as receptors transducing signals on contact with the ECM that
elicit specific behavioral responses such as adhesion, migration,
filopodial extension and, in the case of podocytes, foot process
assembly. Importantly, all of these responses involve cytoskeletal
rearrangement, and there is an emerging understanding of how
integrin-ECM interactions affect cytoskeletal assembly through the
downstream activation of Rho family GTPases (20).
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31-integrin in cytoskeletal organization
of collecting duct epithelial cells in monolayer culture. Past studies
with other epithelial cell types such as keratinocytes had demonstrated
that antibodies blocking function of 31
caused cells to dissociate, with the concomitant loss of the cortical
or submembrane cytoskeleton characteristic of epithelial cells
(7, 8). Collecting duct epithelial cells prepared from kidneys deficient in
31-integrin also were unable to assemble
a cortical cytoskeleton and instead assembled actin stress fibers
(63). In contrast to studies with blocking antibodies, 31-integrin-deficient collecting duct
cells retained cadherin-mediated cell-cell junctions. However, in
31-integrin-deficient cells these
cell-cell junctions were less well organized than in normal epithelial
cells, and there was a decreased association of the cytoskeleton with
cadherin-catenin complexes (63). These results indicate a
role for 31-integrin in organizing
epithelial cortical cytoskeletons and also suggest that
31 regulates the function of cadherins in
epithelial cells.
61.
Once the nephron becomes more fully differentiated,
61-integrin continues to be expressed
along both proximal and distal tubular basement membranes, as well as
by collecting ducts, indicating that it is a major laminin receptor
expressed by tubular epithelial cells (31,
47). Significantly, little if any
64-integrin appears to be
expressed during tubular differentiation, in contrast to epithelial
cells of many other organs (31). The
61-integrin is also expressed transiently
along the GBM, possibly by both podocytes and endothelial cells
(31, 47). In surprising contrast to
3-mutant mice, newborn mice carrying a targeted mutation
of the 6-integrin gene appear to have normal kidneys
(19).
A Role for Integrins in Branching Morphogenesis During Development of the Collecting System?
A role for the extracellular matrix in directing the pattern of branching was suggested by Bernfield and co-workers (5). They suggested that the composition of the basement membrane determined whether epithelial cells would proliferate (see Fig. 2). To the extent that this model might be valid, integrins are obvious candidates to transduce signals to cells on the basis of the composition of the surrounding matrix. Any signals transduced by integrins presumably act coordinately with growth factor signaling (57).
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Kidneys of 31-integrin-deficient newborn
mice also have fewer collecting ducts within the papillary region of
the medulla (32). This is suggestive of a decrease in
branching morphogenesis during early kidney development, although this
phenotype could also be due to either an overall decrease in
proliferation or an increase in apoptosis of epithelial cells during
development. Thus far, efforts to quantitatively compare the latter two
possibilities have not shown significant differences between wild-type
and mutant kidneys (J. Symons and J. Kreidberg, unpublished
observations). Despite the appearance of fewer collecting ducts in
31-deficient kidneys, epithelial cells in
those ducts that are present appear to be normal, except for a thinning
of their basement membranes (63). Two hypotheses that may
explain the development of fewer collecting ducts in
31-integrin-deficient kidneys are
1) a subset of collecting duct cells requires a unique
function of 31; or 2) there is
a quantitative decrease in proliferation or branching in the absence of
31-integrin. Thus far, no subset of
collecting duct cells has been described that expresses
31 to the exclusion of other integrins, a
result more consistent with, but not proving, the latter possibility.
A further unexpected result was obtained on intercrossing
3- and 6-mutant mice (10).
In 3/6 double-null embryos examined at
embryonic day 14, kidney development appears no different
than in 3-only null embryos (10).
Therefore, if some integrin is providing redundant function that allows
limited collecting duct development in
31-deficient embryos, it is unlikely to
be 61 but might still be
21. The genetic targeting of the
2-integrin gene has not yet been reported; thus
conclusions are yet be drawn about the relative importance of
21-integrin in kidney development. Alternatively, it is possible that integrins simply are not crucial for
the development and maintenance of epithelial tubular structures during
early organ development, even though this would otherwise appear to be
highly unlikely.
A study of v-containing integrins in metanephric organ
culture found expression of v3-,
v5-, and
v6-integrins in metanephric tissue
(61). Addition of v-antisense
oligonuleotides or anti-v-blocking antibodies to the
organ cultures resulted in dysgenic growth with decreased branching of
the ureteric bud (61). Similar dysgenic effects result
from the addition of antisense oligonucleotides to fibrillin, a ligand
of v3-integrin, suggesting this
interaction as a crucial one during kidney development
(28). However, the v-integrin-knockout
mouse has apparently normal kidneys (2), so the role of
v-containing integrins in kidney development remains unclear.
Two results from in vitro tissue culture systems suggest that integrins
are indeed important for the early rounds of branching morphogenesis
that occur during metanephric development, despite the failure of
gene-targeting experiments to demonstrate this involvement. When
function-blocking antibodies specific for
61-integrin are added to kidney organ
culture, tubulogenesis is inhibited (15). This is in
marked contrast to the normal kidney development observed in
6-integrin-knockout mice (19). As with
other such discrepancies, it is possible that developing tissues are
better able to compensate for missing proteins when they are deficient from the beginning of embryogenesis, rather than when their function is
acutely blocked by the addition of antibodies, but the mechanistic basis for this difference is unknown. The
61-blocking antibodies also inhibited
branching in cultured submandibular gland, suggesting a generalized
role in branching morphogenesis (26). It has not been
possible to do similar experiments examining the role of other
integrins, as potent function-blocking antibodies that cross-react with
other rodent integrins besides 61 are not available.
An additional model system for studying epithelial development involves
culturing Madin-Darby canine kidney (MDCK) cells in three-dimensional
collagen gels. MDCK cells are derived from canine medullary collecting
ducts, and it was shown several years ago that they form branched
tubular structures in three-dimensional gels on stimulation with
hepatocyte growth factor (HGF) (36). The extent to which
this system serves as a model for branching morphogenesis must be
viewed with caution for the following reasons: 1) HGF- and
c-met (HGF receptor)-knockout mice have normal kidney development;
2) branching appears to be random, as opposed to the
specific patterns observed in vivo; and 3) the tubules that form in gels do not have the appearance of classic tubules in cross
section, although there is some degree of apical-basolateral polarization present. Saelman et al. (55) made elegant use
of this system to examine the role of
21-integrin in tubule formation. They
expressed antisense 2-integrin RNA in MDCK cells to
demonstrate that 21-integrin was required
for tubule formation in collagen gels (55). For this
reason, as well as those discussed above, it will become especially
important to observe the extent of kidney development in
21-integrin-deficient mice, even though
this may require conditional gene targeting if the 2
knockout proves to be early embryonically lethal.
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INTEGRIN EXPRESSION IN ADULT KIDNEY AND THE ROLE OF INTEGRINS IN KIDNEY DISEASE |
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ABSTRACT
INTRODUCTION
INTEGRIN EXPRESSION DURING...
INTEGRIN EXPRESSION IN ADULT...
REFERENCES
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Glomerulus
The31-integrin is the major ECM
receptor expressed by podocytes along the GBM (31,
43). One would presume that this integrin should play an
important role in adhering foot processes to the GBM. To our knowledge,
ultrastructural studies have not been performed thus far to demonstrate
whether 31-integrin is only present where
foot processes contact the GBM, or whether it is continuous along the
entire basal aspect of the podocyte. This will be an important point
for future studies, as cytoskeletal rearrangements that are modulated
by interactions between integrins and the GBM probably play a crucial
role in foot process maturation. Patey et al. (43) also
observed expression of v3-integrin on
podocytes; expression of v-integrins was not examined in
other studies of kidney integrin expression (43). Very
weak staining of 61-integrin has also
been observed on podocytes (31, 43, 47).
Integrins expressed on Bowman's capsule include
11, 31,
61, and v3
(31, 43, 47). The
11-integrin appears to be the most
prominent type expressed on mesangial cells; these cells also express
lesser amounts of 21,
31, and 61
(31, 43, 47). Finally,
endothelial cells, both in the glomerulus and along major vessels,
express 31-,
51-, 61-,
and v-containing integrins (31,
43, 47). Unfortunately, there is little that can be said about the relative significance of these expression patterns. There is generally little understanding of the physiological significance of particular integrin repertoires, other than that this
provides some indication of what might be the significant interactions
with the ECM required of each cell type.
Congential Nephrotic Syndrome
In congenital nephrotic syndromes (CNS) there is a failure to form mature foot processes during glomerulogenesis, leading to severe proteinuria and the clinical manifestations of the nephrotic syndrome soon after birth, including severe edema and hypoalbuminemia. There are striking similarities between the phenotype of3-integrin-knockout mice (32) and CNS. In
addition to the lack of foot processes, there are notable proximal
tubule abnormalities, including the formation of cysts and the
accumulation of cytoplasmic vesicles. In
31-integrin-deficient kidneys, these
proximal tubule lesions are thought to be secondary to glomerular
dysfunction, as proximal tubules do not normally express
31-integrin (31). Although these findings might have suggested 3-integrin as a
candidate gene responsible for some forms of CNS, thus far no genetic
kidney disease has been mapped near the 3-integrin human
chromsomal locus. Indeed, mutations in the gene encoding the novel
protein nephrin, expressed at slit diaphragms between podocyte foot
processes, have been established as the etiology of the Finnish type of
CNS, the best-described form of the disease (29,
54). Moreover, despite the similarities between CNS and
the 3-integrin knockout, loss of
31-integrin appears to be a late event in
glomerulosclerosis, and early nephrotic lesions even appear to show an
increase in immunostaining for
31-integrin (35). Therefore,
if CNS and a deficiency in 31-integrin
affect a common pathway involved in foot process formation, it is most
likely that CNS mutations affect proteins acting downsteam of
31-integrin.
Glomerulonephritis and Chronic Renal Injury
Several studies have demonstrated an increased expression of integrins by glomerular and tubular cells during early phases of glomerulonephritis, by cells forming crescents, and subsequent decreased expression in end-stage lesions (3, 44, 59). Interestingly,v3-integrin was expressed on podocytes in
crescentic glomeruli, suggesting that it may play a role in the
adhesion of crescentic cells (3, 59).
Additionally, expression of v5 is
upregulated on tubular cells in glomerulonephritic kidneys (46).
Abnormalities of glomerular podocytes can be demonstrated in both acute
glomerular injury and in chronic renal diseases. Foot process
effacement, characterized by the collapse of the interdigitating components of podocytes that aid in the formation of a filtration barrier, is seen in glomerular diseases manifesting with proteinuria. Adler et al. (1) demonstrated that intact or F(ab')2
anti-1 antibodies (Ab) had a greater effect than Fab
fragments in an experimental system that measured permeability to
albumin in isolated glomeruli, suggesting that integrin crosslinking is
involved in maintaining the permeability barrier. As opposed to the
developmental abnormality in congenital nephrotic syndrome,
immune-mediated injury is thought to underlie these abnormal podocyte
findings. An experimental model of complement-mediated injury to a
glomerular epithelial cell line demonstrated reversible disruption of
actin filaments that could explain the morphological changes seen in glomerular immune injury (60). Complement-mediated injury
reversibly disrupts glomerular epithelial cell actin microfilaments and
focal adhesions (60). Interestingly, despite their severed
connection to the cytoskeleton, matrix-associated integrins were
preserved in this experimental model. Given the role played by
integrins in the regulation of cytoskeletal organization, their
preservation may be related to the reversibility of this form of
glomerular injury.
Mesangial cell proliferation characterizes numerous forms of acute
glomerular injury; ordered mesangial remodeling is essential to the
restoration of normal glomerular function. Progressive glomerular
disease can manifest with ongoing mesangial cell proliferation and
deposition of extracellular matrix components, leading to glomerulosclerosis and loss of renal function. As mediators of the
interaction between cells and ECM, integrins may play a role in this
delicate balance between ordered growth and excess proliferation. Normal mesangial cells express 11- and
51-integrins; this expression is
increased in proliferative forms of glomerulonephritis (27, 33). Integrin overexpression may be
related to elevated levels of glomerular transforming growth
factor-, which has been detected in association with the upregulated
1-integrins (27, 33).
Chronic forms of renal injury are characterized histologically by
ongoing glomerulosclerosis and advancing interstitial fibrosis with
tubular atrophy. This pattern can be seen as the final common pathway
for most forms of progressive renal disease, from glomerulonephritis to
chronic rejection of transplanted renal allografts. A study of integrin
expression in renal biopsies of patients with chronic renal injury
demonstrated an increased distribution of
51- and v-integrins in
areas with greater degrees of chronic histological damage
(53). These integrins serve as fibronectin receptors, and
this expression pattern is therefore consistent with the notion their
increased expression serves to augment fibronectin assembly as part of
an ongoing fibrotic process. It is also possible that a more complex
regulatory circuit is operative, whereby intracellular signals activate
integrin-mediated matrix assembly on the cell surface by virtue of a
direct effect on the integrin itself, such as inducing a conformation
change that improves its ability to bind ECM ligands. Much more needs
to be learned about this "inside- out" signaling affecting integrin
function (16) to determine whether this is a valid
mechanism in glomerulonephritis and other kidney disease.
Proximal Tubules
The61 receptor appears to be the
major laminin receptor expressed by proximal tubule epithelial cells
(31, 43, 47). Other prominent
laminin receptors, including 21 and
31, have not been detected on proximal tubules.
Distal Tubules
The21-,
31-, and
61-integrins all appear to be expressed
by distal tubules (31, 43, 47).
It remains unclear why distal tubules would require more diverse
integrin expression than proximal tubules. It can be hypothesized that
integrin repertoires affect such parameters as basement membrane
composition, permeability, or the tensile strength of the interactions
between cells and their respective basement membranes. If so, it is
likely that these parameters are different in distinct types of
tubules, thus the requirement for different integrins. Unfortunately,
at this time these possibilities remain matters for speculation.
Collecting Ducts
Similarly to distal tubules,21-,
31-, and
61-integrins also appear to be expressed
by collecting duct epithelial cells (31, 43,
47). Korhonen et al. (31) also detected weak staining of 4-integrins along collecting ducts,
suggesting that some 6 might be heterodimerized with
4- subunit, although this has not been confirmed in
other studies (31).
Acute Tubular Injury
The major interest regarding the role of integrins in tubular injury centers on how modulations in integrin function and localization may be involved in the exfoliation of epithelial cells into the tubular lumen during acute renal failure. A study involving kidney cells in culture showed apical expression of the3-integrin
subunit after oxidative stress (17). This led to
the suggestion that apical expression of integrins may actively be
involved in exfoliation by binding matrix components in tubular lumen.
Zuk et al. (66) have recently published an exhaustive
study of integrin expression in a postischemic-reperfusion model in rat
kidneys. They observed that integrin expression changed from
exclusively basal to basolateral during the first several hours after
ischemic injury. In contrast to the earlier study, however,
they failed to observe apical expression of 1-integrins,
even after tubular lumen were filled with exfoliated material
(66). A small amount of apical expression was observed 120 h after ischemic injury, but by this time tubular injury was already resolving. Zuk et al. present a model in which migration of
integrins from a basal to lateral localization leads to progressive detachment from the basement membrane and exfoliation
(66). As tubular cells regenerate, they pass through a
stage where integrins are expressed on all membranes and subsequently
become polarized on the basal membrane. An important caveat here is
these studies have only examined expression of
1-integrins, leaving open the possibility that other
integrins, such as v3, are expressed apically or are
otherwise involved in exfoliation.
The observation that integrin localization is altered after acute renal
injury prompted studies to test whether peptides that contain the RGD
(arginine-glycine-aspartic acid) sequence would ameliorate the degree
of injury (21, 22). The RGD sequence is found
at sites where a subset of integrins bind components of the
extracellular matrix; these include 51,
81, and v3. RGD sites are not thought to be involved in the interaction of integrins such as 31 and
61 with the basement membrane. Studies by
Goligorsky et al. (22) and Noiri and co-workers
(39, 40), using the ischemic rat kidney
model, showed that adminstration of certain RGD peptides lessened the
degree of tubular injury, as adjudged by the appearance of the urine
sediment, the extent of tubular dilatation, and the creatinine
clearance. An increase in the uptake of labeled RGD peptides by tubular
epithelium after renal injury was also documented (52).
The results of Zuk et al. (66), who failed to observe
apical expression of 1-integrins, raise the question of
whether RGD peptides affect the function of basolaterally localized
integrins. As mentioned above, these studies have only detected
1-integrins, such that
v3-integrin remains a potential target of
RGD peptides. Thus our understanding of the role of integrins in the
pathogenesis of acute renal failure remains incomplete and provides a
ripe area for further study.
A recent study by Noiri et al. (38) provides a possible
mechanistic explanation for the action of RGD peptides (see Fig. 3). They compared renal injury in
wild-type and the osteopontin-deficient mice that were mentioned
previously. Osteopontin contains an RGD site and is a ligand for
81- and
v3-integrins. Ischemia-related renal
dysfunction and pathology were more severe in osteopontin-deficient mice (38). In vitro, osteopontin was protective when
proximal tubular cells were exposed to hypoxic conditions, whereas
osteopontin missing the RGD sequence was not protective
(38). Cytoprotection during hypoxia could also be provided
in vitro by RGD peptides (38). These results suggest that
the RGD sequence is the crucial element within the osteopontin protein
that stimulates processes which prevent cytotoxic injury. A possible
mechanism for the action of osteopontin is suggested by the observation
that osteopontin has been shown to suppress expression of an inducible
nitric-oxide synthase (51, 58), an enzyme
associated with renal injury after ischemia-reperfusion
(6).
|
In addition to their possible causative role in acute tubular damage, integrins may also be involved in mechanisms of repair after acute renal injury. After the exfoliation of tubular cells noted above, recovery of renal function requires a reconstitution of the normal tubular epithelium through proliferation of residual cells. In contradistinction to the proposal that altered integrin localization promotes renal damage through cell sloughing, integrins may also be necessary for the reparative processes that occur after acute tubular injury. Proximal tubular cells exposed to a free radical-generating system that simulates in vivo tubular injury had a diminished proliferative capacity in the presence of inhibitors to integrin function, including, ironically, glycine-RGD peptides similar to those used to limit renal injury due to sloughing of cells (65). Furthermore, injured cells were more likely to undergo apoptosis in the setting of integrin inhibition. Consequently, integrins may play multiple roles in the dynamic arc of acute tubular injury, exacerbating damage in its earliest phases and later promoting repair.
Diabetic Nephropathy
Alterations in integrin expression have been studied in diabetic nephropathy (DN). Similar to what is observed in glomerulonephritis as noted above, expression of integrins in the glomerulus with DN appears to increase during early damage, on epithelial, endothelial, and mesangial cells (25). One study showed this increase to continue during severe DN except for endothelial integrin expression, which returned to normal levels (25). In contrast, a study of the expression of31-integrin by
glomerular cells in diabetic rats showed a decrease in expression of
31 in short- and long-term diabetic
animals (48). Much more work is required to determine whether abnormalities in integrin-mediated signal transduction, particularly as it relates to interactions of integrins with the GBM,
is involved in DN.
Polycystic Kidney Disease
There has been limited examination of changes in integrin expression during the pathogenesis of polycystic kidney disease (PKD). Generation and progressive enlargement of tubular cysts in all forms of PKD are thought to stem from interplay among three basic processes: tubular cell hypertrophy, tubular fluid secretion, and abnormalities related to the tubular cell ECM. Given their status as mediators for reciprocal interactions between the ECM and epithelial cells, integrins can be hypothesized as having a causal role in cyst formation. Alternatively, impairment of integrin-basement membrane interactions could be downstream of more primary abnormalities that lead to cystogenesis. An examination of the expression of severall-integrins in PKD demonstrated irregular expression of
21-, 31-,
and 61-integrins in cystic epithelial
cells (9). Expression of
11-integrin was increased, also
suggesting a possible role for this integrin in cyst formation (9). These changes occurred early in the process of cyst
formation, indicating that a disturbance of interactions between
integrins and tubular membranes may have a causal role in PKD. More
work in this area will be needed to further elucidate a role for
integrins in PKD.
Summary
It is now well established that there is widespread expression of integrins during kidney development and in adult kidneys. Gene-targeting experiments have been informative about locations where individual integrins fulfill a crucial function, most notably81 in interactions between the ureteric
bud and the metanephric mesenchyme, and
31 in glomerulogenesis. In contrast, gene
knockouts of other widely expressed integrin subunits, such as
6 and v, led to seemingly normal kidneys,
suggesting that many integrins may have redundant functions during
nephrogenesis. Moreover, the study of how integrin-mediated signal
transduction is involved in renal epithelial differentiation,
metanephric induction, and mature kidney function is just beginning and
promises to add importantly to our understanding of renal physiology.
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ACKNOWLEDGEMENTS |
|---|
The authors thank Anna Zuk and Michael Goligorsky for helpful discussions.
| |
FOOTNOTES |
|---|
Address for reprint requests and other correspondence: J. A. Kreidberg, Children's Hospital, 300 Longwood Ave., Boston, MA 02115 (E-mail: Kreidberg{at}hub.tch.harvard.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. §1734 solely to indicate this fact.
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REFERENCES |
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ABSTRACT
INTRODUCTION
INTEGRIN EXPRESSION DURING...
INTEGRIN EXPRESSION IN ADULT...
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