title: Inactivation of integrin-β1 prevents the development of polycystic kidney disease after the loss of polycystin-1.
abstract: Dysregulation of polycystin-1 (PC1) leads to autosomal dominant polycystic kidney disease (ADPKD), a disorder characterized by the formation of multiple bilateral renal cysts, the progressive accumulation of extracellular matrix (ECM), and the development of tubulointerstitial fibrosis. Correspondingly, cystic epithelia express higher levels of integrins (ECM receptors that control various cellular responses, such as cell proliferation, migration, and survival) that are characteristically altered in cystic cells. To determine whether the altered expression of ECM and integrins could establish a pathologic autostimulatory loop, we tested the role of integrin-β1 in vitro and on the cystic development of ADPKD in vivo. Compared with wild-type cells, PC1-depleted immortalized renal collecting duct cells had higher levels of integrin-β1 and fibronectin and displayed increased integrin-mediated signaling in the presence of Mn(2+). In mice, conditional inactivation of integrin-β1 in collecting ducts resulted in a dramatic inhibition of Pkd1-dependent cystogenesis with a concomitant suppression of fibrosis and preservation of normal renal function. Our data provide genetic evidence that a functional integrin-β1 is required for the early events leading to renal cystogenesis in ADPKD and suggest that the integrin signaling pathway may be an effective therapeutic target for slowing disease progression.
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; and kim.lee@mssm.edu luca.gusella@mssm.edu.
authors.forename: Kyung
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; and.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Boctor
authors.affiliation: Department of Pathology, University of Miami, Miami, Florida.
authors.forename: Laura M C
authors.initials: LM
authors.lastname: Barisoni
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; and kim.lee@mssm.edu luca.gusella@mssm.edu.
authors.forename: G Luca
authors.initials: GL
authors.lastname: Gusella
mesh_terms: D000818:Animals; D002460:Cell Line; D005355:Fibrosis; D019012:Integrin beta1 / Q000378:metabolism*; D007668:Kidney / Q000473:pathology; D051379:Mice; D007690:Polycystic Kidney Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D019012:Integrin beta1; D050396:TRPP Cation Channels
keywords: autosomal dominant polycystic kidney disease; cell–matrix interactions; fibrosis; genetic renal disease; polycystic kidney disease