Inactivation of integrin-β1 prevents the development of polycystic kidney disease after the loss of polycystin-1.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Lee, K; Boctor, S; Barisoni, LMC; Gusella, GL

Published Date

  • April 2015

Published In

Volume / Issue

  • 26 / 4

Start / End Page

  • 888 - 895

PubMed ID

  • 25145933

Pubmed Central ID

  • PMC4378096

Electronic International Standard Serial Number (EISSN)

  • 1533-3450

Digital Object Identifier (DOI)

  • 10.1681/ASN.2013111179


  • eng

Conference Location

  • United States