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Mesangial cells organize the glomerular capillaries by adhering to the G domain of laminin 5 in the glomerular basement membrane

¹ Renal Division, Department of Internal Medicine
² Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110
³ Institute of Biomedicine/Anatomy Unit, Biomedicum Helsinki, University of Helsinki, Helsinki 00014, Finland

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

In developing glomeruli, laminin 5 replaces laminin 1 in the glomerular basement membrane (GBM) at the capillary loop stage, a transition required for glomerulogenesis. To investigate domain-specific functions of laminin 5 during glomerulogenesis, we produced transgenic mice that express a chimeric laminin composed of laminin 5 domains VI through I fused to the human laminin 1 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 5 is essential for this adhesion. Analysis of an additional chimeric transgene allowed us to narrow the region of the 5 G domain essential for mesangial cell adhesion to 5LG3-5. Finally, in vitro studies showed that integrin ₃ß₁ and the Lutheran glycoprotein mediate adhesion of mesangial cells to laminin 5. Our results elucidate a mechanism whereby mesangial cells organize the glomerular capillaries by adhering to the G domain of laminin 5 in the GBM.

Key Words: mesangium; cell adhesion; kidney glomerulus; integrin ₃ß₁; transgenic mice

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