Mesangial cells organize the glomerular capillaries by adhering to the G domain of laminin alpha5 in the glomerular basement membrane.
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.
Kikkawa
Yamato
Y
Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Virtanen
Ismo
I
Miner
Jeffrey H
JH
D000818:Animals; D001485:Basement Membrane / Q000002:abnormalities* / Q000166:cytology / Q000378:metabolism; D002196:Capillaries / Q000002:abnormalities* / Q000166:cytology / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005260:Female; D005920:Glomerular Mesangium / Q000002:abnormalities* / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007678:Kidney Glomerulus / Q000002:abnormalities* / Q000166:cytology / Q000378:metabolism; D007797:Laminin / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary / Q000235:genetics
D007797:Laminin; D008562:Membrane Glycoproteins; C119013:laminin 10; C097043:laminin alpha5; C084098:laminin A