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Human Molecular Genetics, 2002, Vol. 11, No. 15 1731-1742
© 2002 Oxford University Press

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

Satoru Muto1, Atsu Aiba2, Yuichirou Saito3, Kazuki Nakao4, Kenji Nakamura5, Kyoichi Tomita1, Tadaichi Kitamura1, Masahiko Kurabayashi3, Ryozo Nagai6, Eiji Higashihara7, Peter C. Harris8, Motoya Katsuki9 and Shigeo Horie1,7,*

1Department of Urology, The University of Tokyo, Tokyo 113-8655, Japan, 2Department of Cell Biology, Kobe University, Kobe 650-0017, Japan, 3Second Department of Internal Medicine, Gunma University, Maebashi 371-8511, Japan, 4Riken, Center for Developmental Biology, Kobe 650-0047, Japan, 5Mitsubishi Kasei Institute of Life Sciences, Machida 194-8511, Japan, 6Department of Cardiovascular Medicine, The University of Tokyo, Tokyo 113-8655, Japan, 7Department of Urology, Kyorin University, Mitaka 181-8611, Japan, 8Department of Nephrology, Mayo Clinic, Rochester, MN 55905, USA and 9National Institute for Basic Biology, Okazaki National Research Institutes, Okazaki 444–8585, Japan

Received March 28, 2002; Accepted May 24, 2002

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 ß-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.

* To whom correspondence should be addressed at: Department of Urology, Kyorin University School of Medicine, 6-20-2, Shinkawa, Mitaka, Tokyo, Japan 181-8611. Fax: +81 422428431; Email: shorie-kkr{at}umin.ac.jp


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