Integrin alpha6 maintains the structural integrity of the kidney collecting system

Laminins are a major constituent of the basement membranes of the kidney collecting system. Integrins, transmembrane receptors formed by non-covalently bound alpha and beta subunits, serve as laminin receptors, but their role in development and homeostasis of the kidney collecting system is poorly defined. Integrin alpha 3 beta 1, one of the major laminin receptors, plays a minor role in kidney collecting system development, while the role of a6 containing integrins (alpha 6 beta 1 and alpha 6 beta 4), the other major laminin receptors, is unknown. Patients with mutations in alpha 6 containing integrins not only develop epidermolysis bullosa, but also have abnormalities in the kidney collecting system. In this study, we show that selectively deleting the alpha 6 or beta 4 integrin subunits at the initiation of ureteric bud development in mice does not affect morphogenesis. However, the collecting system becomes dilated and dysmorphic as the mice age. The collecting system in both null genotypes was also highly susceptible to unilateral ureteric obstruction injury with evidence of excessive tubule dilatation and epithelial cell apoptosis. Mechanistically, integrin alpha 6-null collecting duct cells are unable to withstand high mechanical force when adhered to laminin. Thus, we conclude that alpha 6 integrins are important for maintaining the integrity of the kidney collecting system by enhancing tight adhesion of the epithelial cells to the basement membrane. These data give a mechanistic explanation for the association between kidney collecting system abnormalities in patients and epidermolysis bullosa. (C) 2016 Elsevier B.V. All rights reserved.