title: Integrin alpha6 maintains the structural integrity of the kidney collecting system.
abstract: Laminins are a major constituent of the basement membranes of the kidney collecting system. Integrins, transmembrane receptors formed by non-covalently bound α and β subunits, serve as laminin receptors, but their role in development and homeostasis of the kidney collecting system is poorly defined. Integrin α3β1, one of the major laminin receptors, plays a minor role in kidney collecting system development, while the role of α6 containing integrins (α6β1 and α6β4), the other major laminin receptors, is unknown. Patients with mutations in α6 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 α6 or β4 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 α6-null collecting duct cells are unable to withstand high mechanical force when adhered to laminin. Thus, we conclude that α6 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.
authors.affiliation: Division of Nephrology and Hypertension and Vanderbilt Center for Kidney Disease, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Olga M
authors.initials: OM
authors.lastname: Viquez
authors.affiliation: Division of Nephrology and Hypertension and Vanderbilt Center for Kidney Disease, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Eugenia M
authors.initials: EM
authors.lastname: Yazlovitskaya
authors.affiliation: Division of Nephrology and Hypertension and Vanderbilt Center for Kidney Disease, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Tianxiang
authors.initials: T
authors.lastname: Tu
authors.affiliation: Division of Nephrology and Hypertension and Vanderbilt Center for Kidney Disease, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Glenda
authors.initials: G
authors.lastname: Mernaugh
authors.affiliation: Division of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Pablo
authors.initials: P
authors.lastname: Secades
authors.affiliation: Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
authors.forename: Karen K
authors.initials: KK
authors.lastname: McKee
authors.affiliation: Department of Development and Stem Cells, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, Inserm, U964, Illkirch, CNRS, UMR 7104, Illkirch, Université de Strasbourg, Strasbourg, France.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Georges-Labouesse
authors.affiliation: Department of Development and Stem Cells, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, Inserm, U964, Illkirch, CNRS, UMR 7104, Illkirch, Université de Strasbourg, Strasbourg, France.
authors.forename: Adele
authors.initials: A
authors.lastname: De Arcangelis
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Vito
authors.initials: V
authors.lastname: Quaranta
authors.affiliation: Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Yurchenco
authors.affiliation: Division of Nephrology and Hypertension and Vanderbilt Center for Kidney Disease, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Veterans Affairs Hospital, Nashville, TN 37232, USA.
authors.forename: Leslie C
authors.initials: LC
authors.lastname: Gewin
authors.affiliation: Division of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Arnoud
authors.initials: A
authors.lastname: Sonnenberg
authors.affiliation: Division of Nephrology and Hypertension and Vanderbilt Center for Kidney Disease, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Veterans Affairs Hospital, Nashville, TN 37232, USA.
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
authors.affiliation: Division of Nephrology and Hypertension and Vanderbilt Center for Kidney Disease, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Veterans Affairs Hospital, Nashville, TN 37232, USA. Electronic address: roy.zent@vanderbilt.edu.
authors.forename: Roy
authors.initials: R
authors.lastname: Zent
mesh_terms: D000818:Animals; D017209:Apoptosis; D001485:Basement Membrane / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation; D006801:Humans; D039121:Integrin alpha6beta1 / Q000172:deficiency / Q000235:genetics*; D039161:Integrin alpha6beta4 / Q000172:deficiency / Q000235:genetics*; D007685:Kidney Tubules, Collecting / Q000378:metabolism* / Q000473:pathology; D007797:Laminin / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D015398:Signal Transduction; D014513:Ureter / Q000601:surgery; D014517:Ureteral Obstruction / Q000378:metabolism* / Q000473:pathology / Q000601:surgery
chemical_list: D039121:Integrin alpha6beta1; D039161:Integrin alpha6beta4; D007797:Laminin