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Mesangial cells organize the glomerular capillaries by adhering to the G domain of laminin alpha5 in the glomerular basement membrane.

Kikkawa Y, Virtanen I, Miner JH - J. Cell Biol. (2003)

Bottom Line: In addition, podocytes exhibited their typical arrangement in a single cell layer epithelium adjacent to the GBM, but convolution of glomerular capillaries did not occur.Finally, in vitro studies showed that integrin alpha3beta1 and the Lutheran glycoprotein mediate adhesion of mesangial cells to laminin alpha5.Our results elucidate a mechanism whereby mesangial cells organize the glomerular capillaries by adhering to the G domain of laminin alpha5 in the GBM.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.

ABSTRACT
In developing glomeruli, laminin alpha5 replaces laminin alpha1 in the glomerular basement membrane (GBM) at the capillary loop stage, a transition required for glomerulogenesis. To investigate domain-specific functions of laminin alpha5 during glomerulogenesis, we produced transgenic mice that express a chimeric laminin composed of laminin alpha5 domains VI through I fused to the human laminin alpha1 globular (G) domain, designated Mr51. Transgene-derived protein accumulated in many basement membranes, including the developing GBM. When bred onto the Lama5 -/- background, Mr51 supported GBM formation, preventing the breakdown that normally occurs in Lama5 -/- glomeruli. In addition, podocytes exhibited their typical arrangement in a single cell layer epithelium adjacent to the GBM, but convolution of glomerular capillaries did not occur. Instead, capillaries were distended and exhibited a ballooned appearance, a phenotype similar to that observed in the total absence of mesangial cells. However, here the phenotype could be attributed to the lack of mesangial cell adhesion to the GBM, suggesting that the G domain of laminin alpha5 is essential for this adhesion. Analysis of an additional chimeric transgene allowed us to narrow the region of the alpha5 G domain essential for mesangial cell adhesion to alpha5LG3-5. Finally, in vitro studies showed that integrin alpha3beta1 and the Lutheran glycoprotein mediate adhesion of mesangial cells to laminin alpha5. Our results elucidate a mechanism whereby mesangial cells organize the glomerular capillaries by adhering to the G domain of laminin alpha5 in the GBM.

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Laminin α chain switching and its importance during glomerulogenesis. From the S-shaped to the capillary loop stage of glomerular development, the laminin α1 chain (A and B) is replaced by the laminin α5 chain (C and D) in the GBM, though α1 continues to be expressed by proximal tubules seen in B. (E and F) Targeted mutation of Lama5 prevented this developmental transition, resulting in GBM breakdown and failed vascularization of glomeruli. Sections shown are toluidine blue–stained plastic sections of E18.5 control and Lama5 −/− kidneys. S, S-shaped structure; G, glomerulus. Bars: (A and C) 100 μm; (B and D–F) 50 μm.
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fig1: Laminin α chain switching and its importance during glomerulogenesis. From the S-shaped to the capillary loop stage of glomerular development, the laminin α1 chain (A and B) is replaced by the laminin α5 chain (C and D) in the GBM, though α1 continues to be expressed by proximal tubules seen in B. (E and F) Targeted mutation of Lama5 prevented this developmental transition, resulting in GBM breakdown and failed vascularization of glomeruli. Sections shown are toluidine blue–stained plastic sections of E18.5 control and Lama5 −/− kidneys. S, S-shaped structure; G, glomerulus. Bars: (A and C) 100 μm; (B and D–F) 50 μm.

Mentions: As described in previous papers, transitions in laminin isoform deposition are quite dynamic during kidney development and maturation of the GBM (Miner and Sanes, 1994; Miner et al., 1997; Sorokin et al., 1997a). A crucial developmental switch in laminin α chain deposition occurs in the GBM when the laminin α1 chain, which is predominantly expressed in basement membranes of the S-shape body, is replaced by laminin α5 in the capillary loop stage GBM (Fig. 1 , A–D). In Lama5 −/− mutant glomeruli, where this switch cannot occur, the kidney exhibits avascular glomeruli associated with GBM breakdown (Fig. 1, E and F). The GBM breaks down because laminin α1 is eliminated even in the absence of α5 expression, and without a compensating full-length laminin α chain, basement membrane structure cannot be maintained. As a result of GBM breakdown, the cells that comprise the glomerulus––podocytes, endothelial cells, and mesangial cell––are unable to maintain their proper positions adjacent to the GBM, resulting in failed glomerulogenesis (Miner and Li, 2000). This demonstrates the extreme importance of cell–matrix interactions during glomerulogenesis.


Mesangial cells organize the glomerular capillaries by adhering to the G domain of laminin alpha5 in the glomerular basement membrane.

Kikkawa Y, Virtanen I, Miner JH - J. Cell Biol. (2003)

Laminin α chain switching and its importance during glomerulogenesis. From the S-shaped to the capillary loop stage of glomerular development, the laminin α1 chain (A and B) is replaced by the laminin α5 chain (C and D) in the GBM, though α1 continues to be expressed by proximal tubules seen in B. (E and F) Targeted mutation of Lama5 prevented this developmental transition, resulting in GBM breakdown and failed vascularization of glomeruli. Sections shown are toluidine blue–stained plastic sections of E18.5 control and Lama5 −/− kidneys. S, S-shaped structure; G, glomerulus. Bars: (A and C) 100 μm; (B and D–F) 50 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172883&req=5

fig1: Laminin α chain switching and its importance during glomerulogenesis. From the S-shaped to the capillary loop stage of glomerular development, the laminin α1 chain (A and B) is replaced by the laminin α5 chain (C and D) in the GBM, though α1 continues to be expressed by proximal tubules seen in B. (E and F) Targeted mutation of Lama5 prevented this developmental transition, resulting in GBM breakdown and failed vascularization of glomeruli. Sections shown are toluidine blue–stained plastic sections of E18.5 control and Lama5 −/− kidneys. S, S-shaped structure; G, glomerulus. Bars: (A and C) 100 μm; (B and D–F) 50 μm.
Mentions: As described in previous papers, transitions in laminin isoform deposition are quite dynamic during kidney development and maturation of the GBM (Miner and Sanes, 1994; Miner et al., 1997; Sorokin et al., 1997a). A crucial developmental switch in laminin α chain deposition occurs in the GBM when the laminin α1 chain, which is predominantly expressed in basement membranes of the S-shape body, is replaced by laminin α5 in the capillary loop stage GBM (Fig. 1 , A–D). In Lama5 −/− mutant glomeruli, where this switch cannot occur, the kidney exhibits avascular glomeruli associated with GBM breakdown (Fig. 1, E and F). The GBM breaks down because laminin α1 is eliminated even in the absence of α5 expression, and without a compensating full-length laminin α chain, basement membrane structure cannot be maintained. As a result of GBM breakdown, the cells that comprise the glomerulus––podocytes, endothelial cells, and mesangial cell––are unable to maintain their proper positions adjacent to the GBM, resulting in failed glomerulogenesis (Miner and Li, 2000). This demonstrates the extreme importance of cell–matrix interactions during glomerulogenesis.

Bottom Line: In addition, podocytes exhibited their typical arrangement in a single cell layer epithelium adjacent to the GBM, but convolution of glomerular capillaries did not occur.Finally, in vitro studies showed that integrin alpha3beta1 and the Lutheran glycoprotein mediate adhesion of mesangial cells to laminin alpha5.Our results elucidate a mechanism whereby mesangial cells organize the glomerular capillaries by adhering to the G domain of laminin alpha5 in the GBM.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.

ABSTRACT
In developing glomeruli, laminin alpha5 replaces laminin alpha1 in the glomerular basement membrane (GBM) at the capillary loop stage, a transition required for glomerulogenesis. To investigate domain-specific functions of laminin alpha5 during glomerulogenesis, we produced transgenic mice that express a chimeric laminin composed of laminin alpha5 domains VI through I fused to the human laminin alpha1 globular (G) domain, designated Mr51. Transgene-derived protein accumulated in many basement membranes, including the developing GBM. When bred onto the Lama5 -/- background, Mr51 supported GBM formation, preventing the breakdown that normally occurs in Lama5 -/- glomeruli. In addition, podocytes exhibited their typical arrangement in a single cell layer epithelium adjacent to the GBM, but convolution of glomerular capillaries did not occur. Instead, capillaries were distended and exhibited a ballooned appearance, a phenotype similar to that observed in the total absence of mesangial cells. However, here the phenotype could be attributed to the lack of mesangial cell adhesion to the GBM, suggesting that the G domain of laminin alpha5 is essential for this adhesion. Analysis of an additional chimeric transgene allowed us to narrow the region of the alpha5 G domain essential for mesangial cell adhesion to alpha5LG3-5. Finally, in vitro studies showed that integrin alpha3beta1 and the Lutheran glycoprotein mediate adhesion of mesangial cells to laminin alpha5. Our results elucidate a mechanism whereby mesangial cells organize the glomerular capillaries by adhering to the G domain of laminin alpha5 in the GBM.

Show MeSH
Related in: MedlinePlus