A Pkd1-Fbn1 genetic interaction implicates TGF-β signaling in the pathogenesis of vascular complications in autosomal dominant polycystic kidney disease.
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 of Marfan 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.
Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland;
Dongyan
D
Liu
Connie J
CJ
Wang
Daniel P
DP
Judge
Marc K
MK
Halushka
Jie
J
Ni
Jennifer P
JP
Habashi
Javid
J
Moslehi
Djahida
D
Bedja
Kathleen L
KL
Gabrielson
Hangxue
H
Xu
Feng
F
Qian
David
D
Huso
Harry C
HC
Dietz
Gregory G
GG
Germino
Terry
T
Watnick
D000818:Animals; D004195:Disease Models, Animal; D004843:Epistasis, Genetic; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D056726:Genetic Association Studies; D057895:Haploinsufficiency; D006579:Heterozygote; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics*; D009154:Mutation; D016891:Polycystic Kidney, Autosomal Dominant / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D050396:TRPP Cation Channels / Q000172:deficiency / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014652:Vascular Diseases / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D054392:Adipokines
D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D050396:TRPP Cation Channels; D016212:Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse