TY - JOUR
T1 - Pioglitazone improves the phenotype and molecular defects of a targeted Pkd1 mutant
AU - Muto, Satoru
AU - Aiba, Atsu
AU - Saito, Yuichirou
AU - Nakao, Kazuki
AU - Nakamura, Kenji
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
N1 - Funding Information:
We thank K. Katsuki and T. Etoh for their excellent technical assistance, Y. Chida and M. Emoto for cell culture work and H. Yoshikura, K. Kurokawa, Y. Asano, T. Fujita, T. Igarashi, S. Sasaki, K. Miyazono, T. Suda, T. Koike and R. Nishinakamura for critical comments on this study. This work was supported in part by grants from the Ministry of Health, Labor and Welfare, and the Ministry of Education, Culture, Sports Science and Technology of Japan.
PY - 2002/7/15
Y1 - 2002/7/15
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/11.15.1731
DO - 10.1093/hmg/11.15.1731
M3 - Article
C2 - 12095915
AN - SCOPUS:0037098955
SN - 0964-6906
VL - 11
SP - 1731
EP - 1742
JO - Human molecular genetics
JF - Human molecular genetics
IS - 15
ER -