A Pkd1-Fbn1 genetic interaction implicates TGF-β signaling in the pathogenesis of vascular complications in autosomal dominant polycystic kidney disease

Dongyan Liu, Connie J. Wang, Daniel P. Judge, Marc K. Halushka, Jie Ni, Jennifer P. Habashi, Javid Moslehi, Djahida Bedja, Kathleen L. Gabrielson, Hangxue Xu, Feng Qian, David Huso, Harry C. Dietz, Gregory G. Germino, Terry Watnick*

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of renal failure that is due to mutations in two genes, PKD1 and PKD2. Vascular complications, including aneurysms, are a well recognized feature of ADPKD, and a subgroup of families exhibits traits reminiscent ofMarfan syndrome (MFS). MFS is caused by mutations in fibrillin-1 (FBN1), which encodes an extracellular matrix protein with homology to latent TGF-β binding proteins. It was recently demonstrated that fibrillin-1 deficiency is associated with upregulation of TGF-β signaling. We investigated the overlap between ADPKD and MFS by breeding mice with targeted mutations in Pkd1 and Fbn1. Double heterozygotes displayed an exacerbation of the typical Fbn1 heterozygous aortic phenotype. We show that the basis of this genetic interaction results from further upregulation of TGF-β signaling caused by Pkd1 haploinsufficiency. In addition, we demonstrate that loss of PKD1 alone is sufficient to induce a heightened responsiveness to TGF-β. Our data link the interaction of two important diseases to a fundamental signaling pathway.

Original languageEnglish
Pages (from-to)81-91
Number of pages11
JournalJournal of the American Society of Nephrology
Volume25
Issue number1
DOIs
Publication statusPublished - Jan 2014
Externally publishedYes

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