Article |
Address correspondence to Jeffrey H. Miner, Washington University School of Medicine, Renal Division, Box 8126, 660 South Euclid Ave., St. Louis, MO 63110. Tel.: (314) 362-8235. Fax: (314) 362-8237. E-mail: minerj{at}pcg.wustl.edu
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Abstract |
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Key Words: mesangium; cell adhesion; kidney glomerulus; integrin 3ß1; transgenic mice
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Introduction |
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Genetic inactivation of laminin chains has also demonstrated that they have specific functions. Mutation in laminin
2 results in congenital muscular dystrophy (Helbling-Leclerc et al., 1995). Mutations in laminin-5 (
3ß3
2) subunits lead to junctional epidermolysis bullosa, a severe skin blistering disease (Pulkkinen and Uitto, 1999). Targeted deletion of laminin
4 leads to impaired microvessel maturation and aberrant localization of neuromuscular synaptic specializations (Patton et al., 2001; Thyboll et al., 2002). We have shown that mice lacking laminin
5 die during late embryogenesis with several developmental defects, including defects in neural tube closure, digit separation, placentation, and kidney and lung development (Miner et al., 1998; Miner and Li, 2000; Nguyen et al., 2002).
In the kidney, basement membranes serve both as structural barriers for tubular epithelia and as a component of the glomerular filter. The glomerular basement membrane (GBM) contains an atypical assortment of basement membrane protein isoforms, including laminin-11 (5ß2
1) and collagen
3
5(IV) (Miner, 1998, 1999). There are transitions in the basement membrane component isoforms that are deposited in the developing GBM (Miner, 1998). During glomerulogenesis, transition of laminin isoforms is especially drastic (Miner et al., 1997; Sorokin et al., 1997a). The nascent GBM initially contains laminin-1 (
1ß1
1) and laminin-8 (
4ß1
1), and laminin-10 (
5ß1
1) joins them at the S-shape stage. By the capillary loop stage, laminin-1 is eliminated from the GBM, and then laminin-9 (
4ß2
1) and laminin-11 (
5ß2
1) begin to accumulate. At maturity, only components of laminin-11 are detected in the GBM (Miner, 1998, 1999). We have previously shown that mice lacking laminin
5 exhibit avascular glomeruli associated with breakdown of the GBM during glomerulogenesis (Miner and Li, 2000). This defect correlates with failure of the developmental switch in laminin
chain deposition in which
5 replaces
1 in the GBM at the capillary loop stage. However, the specific role of laminin
5 in the glomerulus is still undefined.
To investigate domain-specific functions of laminin 5 in developing glomeruli, we analyzed transgenic mice that express chimeric laminin
chains: Mr51 is composed of laminin
5 domains VI through I fused to the human laminin
1 G domain; and Mr5G2 is composed of
5 domains VI through LG2 fused to human
1LG3-5. These chimeras were expressed on the genetic background of the laminin
5 knockout (Lama5 -/-). The developing kidney was analyzed by immunohistochemistry and transmission electron microscopy. We found that the adhesion of mesangial cells to the GBM via the G domain of laminin
5 plays a key role in capillary loop formation during glomerular development. In vitro studies suggested that integrin
3ß1 and Lu are the receptors that mediate binding of mesangial cells to laminin
5.
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Results |
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Identification of cell types in glomerular structures
To further investigate the effects of Mr51 and Mr5G2 on glomerulogenesis, we used cell typespecific antibodies to identify the three cell types found in glomeruli. Frozen sections of E17.5 control, Lama5 -/-, Lama5 -/-; Mr51, and Lama5 -/-; Mr5G2 kidneys were stained with antibodies to WT1, platelet endothelial cell adhesion molecule (PECAM), and desmin to label podocytes, endothelial cells, and mesangial cells, respectively (Fig. 4, green), and doubly labeled with an antibasement membrane antibody (Fig. 4, red). In the control, podocytes were observed in a single cell layer epithelium adjacent to the glomerular capillaries (Fig. 4 A), and mesangial cells, which provide tension to maintain the glomerular capillary loop structure, were found associated with endothelial cells in the interior of the glomerulus (Fig. 4 I). In the Lama5 -/- mutant, the podocytes were in disarray, and the endothelial cells and mesangial cells were extruded from glomerulus, as we showed previously (Miner and Li, 2000; Fig. 4, B, F, and J). In Lama5 -/-; Mr51 glomeruli, the transgene-derived chimeric laminin chain partially rescued the defects observed in the mutant. The podocytes were arranged in a single cell layer (Fig. 4 C), and the endothelial cells and mesangial cells were localized in the interior of the glomerulus, similar to the control (Fig. 4, G and K). These results suggest that the COOH-terminal portion of laminin 5 is dispensable for the assembly of the GBM and arrangement of podocytes. However, the great reduction in capillary looping (Fig. 4, C and K) is indicative of a mesangial cell defect because a similar phenotype has been observed in the total absence of mesangial cells in mice lacking either PDGF B or PDGF receptor ß (Lindahl et al., 1998). Lama5 -/-; Mr5G2 glomeruli exhibited a very similar aberrant glomerular phenotype (Fig. 4, D, H, and L).
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Molecular composition of the Lama5 -/-; Mr51 glomerular basement membrane
The distended capillaries observed upon substitution of Mr51 transgenederived protein for endogenous 5 could result from secondary defects in basement membrane composition. For example, Kostka et al. (2001) recently reported that 1040% of glomeruli in fibulin-1deficient mice exhibit a similar capillary malformation. Thus, the distended capillaries in Lama5 -/-; Mr51 glomeruli could be secondary to the failure of fibulin-1 to incorporate into the GBM. To investigate whether deposition of fibulin-1 or other GBM components was altered in Lama5 -/-; Mr51 glomeruli, we stained E17.5 kidney sections from control and Lama5 -/-; Mr51 fetuses with a panel of antibodies to GBM proteins (Fig. 6; unpublished data). Fibulin-1 was detected in both the GBM and the mesangial matrix on the Lama5 -/-; Mr51 background, suggesting that the distended capillary loops were not secondary to the absence of fibulin-1. We also examined the expression of fibulin-2, agrin, nidogen-1/entactin-1, nephronectin, perlecan, and the collagen
3(IV) and
4(IV) chains, and in no case was there a significant difference between control and Lama5 -/-; Mr51 glomeruli (Fig. 6). Again, this suggested that the defects observed in Lama5 -/-; Mr51 glomeruli are not due to the disappearance of other GBM or mesangial matrix components. However, we did find greatly reduced levels of the laminin ß2 chain (Fig. 7, E and G), whereas laminin ß1 was present in both control and Lama5 -/-; Mr51 maturing glomeruli (Fig. 7, A and C).
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Adhesion of mesangial cells to laminins in vitro
To further investigate interactions between mesangial cells and the laminin 5 G domain, we turned to in vitro adhesion assays that used primary human and rat mesangial cells and purified laminin preparations. We have not yet been able to isolate laminin trimers containing the chimeric
chains, and G domain preparations were not available, so we chose to use commercially available laminins. First, we compared the abilities of laminin-10/11 (
5ß1/2
1) and laminin-1 (
1ß1
1) to promote adhesion of mesangial cells. Quantitative analysis of both human and rat mesangial cell adhesion to surfaces coated with increasing concentrations of these proteins showed that laminin-10/11 had higher cell adhesion activity than laminin-1, especially at the lower protein concentrations (Fig. 8, A and B). In addition, the cells spread less well on laminin-1 than they did on laminin-10/11 (unpublished data). These data provide an explanation as to why mesangial cells adhere poorly to GBM containing the
1 G domain (Fig. 5, F and J) but adhere well to normal GBM containing the
5 G domain (Fig. 5, D and I). We believe that these in vitro data using laminin trimers justify our conclusions concerning adhesiveness of G domains because in vivo mesangial cells adhere to wild-type
5 but not to Mr51, which contains
5 domains VI through I. Thus, adhesion to laminin-10/11 trimers is likely mediated primarily by the
5 G domain.
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Recently, it has been reported that Lu, a member of the Ig superfamily, is a potential nonintegrin receptor for the laminin 5 chain (Lee et al., 1998; Udai et al., 1998; Parsons et al., 2001). A splice variant of Lu present in humans that should also bind laminin
5 is known as basal cell adhesion molecule (El Nemer et al., 1998; Zen et al., 1999). In our previous studies, we showed that Lu is expressed on the surface of a subset of muscle and epithelial cells in diverse tissues adjacent to basement membranes containing the laminin
5 chain (Moulson et al., 2001). We have also identified Lu to be a specific receptor for laminin
5 via binding to the
5 G domain by using a recombinant form of soluble Lu (sol-Lu) that contains only the Lu extracellular domain; in addition, the presence of
5LG3 was required for binding (Kikkawa et al., 2002). Lu was coexpressed with integrin
3 on mouse mesangial cells in vivo (unpublished data). To examine whether Lu is also involved in adhesion of mesangial cells to laminin
5, sol-Lu was used in adhesion/inhibition assays (Fig. 8 D). In theory, sol-Lu should bind Lu binding sites on laminin
5 and prevent the Lu present on mesangial cells from interacting with
5. Although sol-Lu alone had no effect on mesangial cell adhesion to laminin-10/11, a significant inhibitory effect was observed when it was combined with the antiintegrin ß1 antibody (Fig. 8 D). Thus, Lu may be a secondary receptor for adhesion of mesangial cells to laminin-10/11. In addition, the fact that sol-Lu did not enhance the antiintegrin
3 antibody inhibition suggests that there may be another integrin
subunit that is involved.
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Discussion |
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Expression of the Mr51, and presumably Mr5G2, chimeric chains on the Lama5 -/- background was able to rescue the breakdown of the GBM (Fig. 5) that normally occurs in Lama5 -/- glomeruli when laminin
1 is eliminated (Miner and Li, 2000). The mechanism of
1 elimination is unknown; but if it is not purely transcriptional, then it must somehow be selective for
1 because
5 is not eliminated. It is likely that primary sequence differences or domain structural differences account for the selective elimination of
1. The G domain of
1, present in Mr51, could have carried a signal for elimination, but our results suggest this not to be the case because Mr51 was not eliminated. We are continuing to investigate this interesting issue using additional
chain transgenes.
The major defect in the Lama5 -/-; Mr51 and Lama5 -/-; Mr5G2 embryos was ballooning of the glomerular capillaries. This same defect was observed in mice lacking mesangial cells due to absence of PDGFB/PDGF receptor ß signaling (Lindahl et al., 1998). However, in our case, mesangial cells were clearly present (Fig. 4, K and L, and Fig. 5 J), so we concluded that they must not be adhering properly to the GBM to maintain capillary looping. As the only known differences between normal and Lama5 -/-; Mr51/Mr5G2 GBMs are the G domain substitutions, and laminin chain G domains have been shown to harbor recognition sites for numerous cell adhesion receptors (Colognato and Yurchenco, 2000), we hypothesized that mesangial cells normally adhere to the
5 G domain but were unable to adhere tightly to either the complete
1 G domain or to
1 LG35. Our in vitro studies confirmed that both human and rat mesangial cells adhere better to
5-containing laminins than to
1-containing laminin (Fig. 8, A and B).
With regard to mechanisms for mesangial adhesion to the 5 G domain, mesangial cells express several ß1 integrins, including
1ß1,
2ß1,
3ß1,
5ß1,
6ß1, and
8ß1 (Gauer et al., 1997; Sterk et al., 1998; unpublished observations). Furthermore, immuno-EM studies have shown that ß1-containing integrins are concentrated at the mesangial cell surface adjacent to the GBM and the mesangial matrix (Kerjaschki et al., 1989). Antibody inhibition studies demonstrated that integrin
3ß1 plays a major role in mesangial cell adhesion to laminin-10/11 (Fig. 8). In support of this, the glomerular capillaries of Itga3 -/- kidneys are dilated (Kreidberg et al., 1996), suggesting a defect in mesangial adhesion to the GBM but the fact that the capillaries are not ballooned suggests that another receptor normally cooperates with
3ß1 and is able to partially compensate in Itga3 -/- mesangial cells. We found that Lu is expressed on mouse mesangial cells and cooperates with ß1 integrins to mediate adhesion in vitro (unpublished data; Fig. 8 D). The fact that Lu was found to be involved is consistent with the fact that Mr5G2 does not support capillary loop formation in vivo, because we have shown that sol-Lu does not bind Mr5G2 (Kikkawa et al., 2002). Lu mutant mice being generated in our laboratory will allow us to more directly address the function of Lu in glomerulogenesis.
An important issue to consider here is the relationship of mesangial cells with laminins in the mesangium, a nonbasement membrane ECM, which mesangial cells secrete and in which they are embedded. Several different laminins are found in the mesangium, including substantial amounts of laminins-1 (1ß1
1), -2 (
2ß1
1), and -10 (
5ß1
1), but others can be detected at lower levels (Miner, 1999). It has not been possible to determine the relative levels of these laminins, but one would suspect that, based on our findings, decreased levels of laminin-10 or increased levels of laminin-1, as might occur in disease states, could correlate with reduced adhesion of mesangial cells to the mesangial matrix. On the other hand, the fact that mesangial cells are almost totally surrounded by their matrix may make this issue irrelevant, as weaker adhesion may be tolerated, both in disease and in normal states. This would be in contrast to the relationship of mesangial cells to the GBM, with which they make contact only at the bases of the capillary loops. A more robust adhesion to the GBM may be necessary in this setting of limited contact in order to counteract the force of blood pressure. Therefore, interaction with the G domain of
5, normally the only
chain in the GBM, would ensure a tight adhesion.
Two other laminin mutant mice with kidney defects have been described. In mice lacking laminin ß2, the ß1 chain compensates and allows an ultrastructurally normal basement membrane to form. However, the glomerular filter fails as a barrier to plasma proteins, and the mice die at 3 wk of age with massive proteinuria (Noakes et al., 1995). No defects in capillary looping were observed, consistent with the fact that laminin 5, as part of laminin-10 (
5ß1
1), is present in the GBM (unpublished observations); thus, mesangial cells should still be capable of binding to the GBM and maintaining capillary looping. On the other hand, mice lacking the binding site for nidogen on laminin
1 exhibit glomerular capillary aneurysms similar to the ballooned capillaries we have reported here. The aneurysms were associated with GBM discontinuities (Willem et al., 2002), and we suggest that these GBM defects prevent mesangial cells from adhering and maintaining the integrity of the capillary loops.
Integrin 3ß1 is expressed basally on podocytes (Korhonen et al., 1990; Kreidberg et al., 1996), yet detachment of podocytes from the GBM in Lama5 -/- Mr51/Mr5G2 glomeruli, as occurred with mesangial cells, was not observed. There are two possibilities to explain this. First, integrin
3ß1 on podocytes may serve primarily as a signal transducing receptor rather than as an anchoring one. Dystroglycan is also expressed on podocytes but not on mesangial cells (unpublished data), and together with Lu, this may be sufficient for adhesion of podocytes to the GBM. Second, podocytes and mesangial cells may be adhering only weakly to the chimeric laminins through integrin
3ß1. This may be sufficient for long-term adhesion of podocytes to the GBM but not for mesangial cells. Capillary looping was evident in immature Lama5 -/-; Mr51/Mr5G2 glomeruli, but mesangial cell adhesion to the GBM was apparently too weak to counteract the force of blood pressure, leading to de-adhesion and capillary ballooning. In support of this is our finding that adhesion activity of laminin-10/11 (
5ß1/2
1) was stronger than that of laminin-1 (
1ß1
1) for both human and rat mesangial cells (Fig. 8, A and B).
In conclusion, the laminin 5 chain plays a crucial role in maintaining glomerular capillary loop structure. We mapped the adhesive site in vivo to the LG35 modules of the G domain. Adhesion of mesangial cells to the laminin
5 G domain is mediated by integrin
3ß1 and Lu. Mesangial cells express contractile proteins and are similar to smooth-muscle cells. Their frequency and extent of contraction in response to vasoactive substances are thought to determine the glomerular filtration rate. It is interesting to speculate that defective interactions between mesangial cells and laminin
5 in the GBM may be a feature of diverse glomerulopathies in the adult kidney.
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Materials and methods |
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Preparation of the chimeric laminin constructs
Preparation of the chimeric laminin chains, designated Mr51 and Mr5G2, has been described in Kikkawa et al. (2002). Both chimeric laminin cDNAs were cloned into a modified version of the widely active expression vector miw, which contains the RSV LTR inserted into the chicken ß-actin promoter (Suemori et al., 1990).
Generation of knockout and transgenic mice
Production of Lama5 mutant mice and of transgenic mice expressing a full-length laminin 5 transgene or the chimeric laminin transgenes has been described previously (Miner et al., 1998; Moulson et al., 2001; Kikkawa et al., 2002). Five independent Mr51 lines, all of which gave similar results, and one Mr5G2 line were produced.
Immunohistochemistry
For immunohistochemistry, mouse embryos from timed matings were frozen whole by immersing in OCT compound and quick-freezing in 2-methylbutane cooled in a dry ice ethanol bath. Sections were cut at 7 µm in a cryostat and air-dried. For staining, sections were blocked in 10% normal goat serum and incubated with primary antibody. All antibody incubations were in PBS containing 1% BSA, and all washes were in PBS. Secondary antibodies were conjugated to FITC (ICN Biomedicals) or Cy3 (CHEMICON International, Inc.). After several washes, sections were mounted in 90% glycerol containing 0.1x PBS and 1 mg/ml p-phenylenediamine. Sections were examined through a microscope (Eclipse E800; Nikon). Images were captured with a Spot 2 cooled color digital camera (Diagnostic Instruments) using Spot Software Version 2.1. Images were imported into Adobe Photoshop 5.0 and Adobe Illustrator 9.0 for processing and layout.
For semi-thin and thin sectioning, embryonic kidneys were fixed in 4% paraformaldehyde, 4% glutaraldehyde in 0.1 M cacodylate buffer and processed as described previously (Noakes et al., 1995). 2-µm sections were cut with a glass knife and stained with toluidine blue for light microscopy. Thin sections were cut with a diamond knife and stained with lead citrate plus uranyl acetate for transmission electron microscopy. Reagents were obtained from Polysciences Inc.
Cell culture and adhesion assay
Normal human mesangial cells were purchased from Cambrex Life Science Corporation. Cells were grown in MsGM medium supplied by Cambrex Life Science Corporation and used within seven passages. Primary rat mesangial cells were provided by Q. Yu and A.R. Morrison (Washington University School of Medicine). Cells were grown in DME supplemented with 20% FBS, 10 µg/ml insulin, 1 mM glutamate, and 1 mM sodium pyruvate (Invitrogen) and used within seven passages. Adhesion assays were performed as described previously (Kikkawa et al., 2000). In brief, 20 µg/ml of commercial laminin-10/11 was coated onto a 96-well plate (Nunc) at 37°C for 1 h. The wells were blocked with 1% BSA. Mesangial cells were trypsinized and allowed to recover in serum-free medium for 30 min and 100 µl of mesangial cells at 105 cells/ml in DME were added to the wells. After a 1-h incubation, the attached cells were stained with 0.2% crystal violet in 20% methanol for 10 min, 100 µl of 1% SDS was added to dissolve the cells, and absorbance was measured at 570 nm by VERSAmax (Molecular Devices). To identify the receptors for laminin-10/11, 10 µg/ml of monoclonal antibodies against different integrins and the recombinant sol-Lu protein were preincubated individually with mesangial cells in a volume of 50 µl of serum-free DME (5 x 103 cells/well) at room temperature for 15 min. The preincubated cells were transferred to plates coated with laminin-10/11 and incubated further at 37°C for 20 min. After incubation, the attached cells were stained with 0.2% crystal violet in 20% methanol for 10 min and counted under the microscope.
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Acknowledgments |
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This work was supported by grants to J.H. Miner from the National Institutes of Health (P50DK045181 and R01GM060432) and in part by research grants from the March of Dimes (6-FY99-232 and 1-FY02-192).
Submitted: 26 November 2002
Revised: 18 February 2003
Accepted: 18 February 2003
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