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 J.H.J Cell Biol., 2003

In developing glomeruli, laminin alpha-5 (laminin-521 and -511) replaces laminin alpha-1 (laminin-111) in the glomerular basement membrane (GBM) at the capillary loop stage, a transition required for glomerulogenesis. By the capillary loop stage, laminin-111 is eliminated and at maturity, only laminin-521 is detected in the GBM where it plays a crucial role in maintaining glomerular capillary loop structures. To investigate domain-specific functions of laminin alpha5 during glomerulogenesis, the authors produced transgenic mice that express chimeric laminin composed of laminin alpha-5 domains fused to the human laminin alpha-1 globular (G) domain (Mr51). 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 the 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, suggesting that the G domain of laminin alpha-5 is essential for mesangial adhesion. Finally, in vitro studies showed that integrin alpha3beta1 and the Lutheran glycoprotein mediate adhesion of mesangial cells to laminin alpha-5. These results elucidate a mechanism whereby mesangial cells organize the glomerular capillaries by adhering to laminin alpha-5 in the GBM.