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(American Journal of Pathology. 2003;163:1791-1800.)
© 2003 American Society for Investigative Pathology

ß4 Integrin and Laminin 5 Are Aberrantly Expressed in Polycystic Kidney Disease

Role in Increased Cell Adhesion and Migration

Dominique Joly*, Viviane Morel*, Aurélie Hummel*, Antonella Ruello*, Patrick Nusbaum*, Natacha Patey{dagger}, Laure-Hélène Noël*, Patricia Rousselle{ddagger} and Bertrand Knebelmann*§

From INSERM 507,* the Departments of Nephrology§ and Pathology,{dagger} Necker Hospital, and Université Paris V, Paris; and Institut de Biologie et Chimie des Protéines,{ddagger} CNRS UMR 5086, Université Lyon, Lyon, France

Extracellular matrix alterations have been suggested to be part of the early events occurring in Autosomal Dominant Polycystic Kidney Disease (ADPKD), a disease characterized by formation of renal cysts and progressive renal failure. Here we report that cDNA array analysis identified ß4 integrin aberrant expression in ADPKD cells. Furthermore, laminin 5 (Ln-5), the main {alpha}6ß4 integrin ligand, was also found to be abnormally expressed in ADPKD. Studies performed with ADPKD cyst-lining epithelial cells (CC) by comparison with normal tubular cells indicate that integrin {alpha}6ß4-Ln-5 interactions are involved in cellular events of potential importance for cystogenesis: 1) laminin 5 is a preferential adhesion substrate for CC, mainly through {alpha}6ß4 interaction, 2) CC increased haptotactic and chemotactic motility depends on the presence of Ln-5 and requires integrin {alpha}3ß1 cooperation, and 3) CC haptotactic or chemotactic migration is specifically increased by mAb-mediated ß4 integrin ligation, through an {alpha}3ß1 integrin-dependent and independent pathway, respectively. These results highlight the role of Ln-5 and {alpha}6ß4 integrin in adhesive and motility properties of cyst-lining epithelial cells, and further suggest that integrins and extracellular matrix modifications may be of general relevance to kidney epithelial cell cyst formation.




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