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

Satoru Muto, Atsu Aiba, Yuichirou Saito, Kazuki Nakao, Kenji Nakamura, Kyoichi Tomita, Tadaichi Kitamura, Masahiko Kurabayashi, Ryozo Nagai, Eiji Higashihara, Peter C Harris, Motoya Katsuki, Shigeo Horie

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Abstract

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 β-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.

Original languageEnglish (US)
Pages (from-to)1731-1742
Number of pages12
JournalHuman Molecular Genetics
Volume11
Issue number15
StatePublished - Jul 15 2002

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pioglitazone
Autosomal Dominant Polycystic Kidney
Phenotype
Kidney
Embryonic Structures
Thiazolidinediones
Catenins
Homozygote
Cadherins
Epidermal Growth Factor Receptor
Tyrosine
Exons
Edema
Phosphorylation
Mutation
Membranes

ASJC Scopus subject areas

  • Genetics

Cite this

Muto, S., Aiba, A., Saito, Y., Nakao, K., Nakamura, K., Tomita, K., ... Horie, S. (2002). Pioglitazone improves the phenotype and molecular defects of a targeted Pkd1 mutant. Human Molecular Genetics, 11(15), 1731-1742.

Pioglitazone improves the phenotype and molecular defects of a targeted Pkd1 mutant. / Muto, Satoru; Aiba, Atsu; Saito, Yuichirou; Nakao, Kazuki; Nakamura, Kenji; Tomita, Kyoichi; Kitamura, Tadaichi; Kurabayashi, Masahiko; Nagai, Ryozo; Higashihara, Eiji; Harris, Peter C; Katsuki, Motoya; Horie, Shigeo.

In: Human Molecular Genetics, Vol. 11, No. 15, 15.07.2002, p. 1731-1742.

Research output: Contribution to journalArticle

Muto, S, Aiba, A, Saito, Y, Nakao, K, Nakamura, K, Tomita, K, Kitamura, T, Kurabayashi, M, Nagai, R, Higashihara, E, Harris, PC, Katsuki, M & Horie, S 2002, 'Pioglitazone improves the phenotype and molecular defects of a targeted Pkd1 mutant', Human Molecular Genetics, vol. 11, no. 15, pp. 1731-1742.
Muto S, Aiba A, Saito Y, Nakao K, Nakamura K, Tomita K et al. Pioglitazone improves the phenotype and molecular defects of a targeted Pkd1 mutant. Human Molecular Genetics. 2002 Jul 15;11(15):1731-1742.
Muto, Satoru ; Aiba, Atsu ; Saito, Yuichirou ; Nakao, Kazuki ; Nakamura, Kenji ; Tomita, Kyoichi ; Kitamura, Tadaichi ; Kurabayashi, Masahiko ; Nagai, Ryozo ; Higashihara, Eiji ; Harris, Peter C ; Katsuki, Motoya ; Horie, Shigeo. / Pioglitazone improves the phenotype and molecular defects of a targeted Pkd1 mutant. In: Human Molecular Genetics. 2002 ; Vol. 11, No. 15. pp. 1731-1742.
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AU - Tomita, Kyoichi

AU - Kitamura, Tadaichi

AU - Kurabayashi, Masahiko

AU - Nagai, Ryozo

AU - Higashihara, Eiji

AU - Harris, Peter C

AU - Katsuki, Motoya

AU - Horie, Shigeo

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