Pioglitazone improves the phenotype and molecular defects of a targeted Pkd1 mutant

Hum Mol Genet. 2002 Jul 15;11(15):1731-42. doi: 10.1093/hmg/11.15.1731.


Mutations of either PKD1 or PKD2 are associated with autosomal dominant polycystic kidney disease (ADPKD). The molecular function of the gene product of PKD1, polycystin-1, in vitro has been elucidated recently, but the molecular pathological consequences of the loss of polycystin-1 in vivo have remained unclear. We have generated a mouse with a targeted deletion of exons 2-6 of Pkd1 to study the molecular defects in Pkd1 mutants. Homozygote embryos (Pkd1(-/-)) developed hydrops, cardiac conotruncal defects and renal cystogenesis. Total protein levels of beta-catenin in heart and kidney and c-MYC in heart were decreased in Pkd1(-/-) embryos. In the kidneys of Pkd1(-/-), the expression of E-cadherin and PECAM in basolateral membranes of renal tubules was attenuated, and tyrosine phosphorylation of epidermal growth factor receptor and Gab1 were constitutively enhanced when cystogenesis started on embryonic day (E) 15.5-16.5. Maternally administered pioglitazone, a thiazolidinedione compound, resolved these molecular defects of Pkd1(-/-). Treatment with pioglitazone improved survival of Pkd1(-/-) embryos and ameliorated the cardiac defects and the degree of renal cystogenesis. Long-term treatment with pioglitazone improved the endothelial function of adult Pkd1(+/-). These data indicated that molecular defects observed in Pkd1(-/-) embryos contributed to the pathogenesis of ADPKD and that thiazolidinediones had a compensatory effect on the pathway affected by the loss of polycystin-1. Pathways activated by thiazolidinediones may provide new therapeutic targets in ADPKD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytoskeletal Proteins / metabolism
  • Endothelium / physiopathology
  • Kidney / physiopathology
  • Mice
  • Phenotype
  • Pioglitazone
  • Polycystic Kidney, Autosomal Dominant / drug therapy*
  • Polycystic Kidney, Autosomal Dominant / genetics*
  • Polycystic Kidney, Autosomal Dominant / pathology
  • Polycystic Kidney, Autosomal Dominant / physiopathology
  • Proteins / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Sequence Deletion
  • TRPP Cation Channels
  • Thiazoles / pharmacology*
  • Thiazolidinediones*
  • Trans-Activators / metabolism
  • beta Catenin


  • CTNNB1 protein, mouse
  • Cytoskeletal Proteins
  • Proteins
  • Proto-Oncogene Proteins c-myc
  • TRPP Cation Channels
  • Thiazoles
  • Thiazolidinediones
  • Trans-Activators
  • beta Catenin
  • polycystic kidney disease 1 protein
  • Pioglitazone