title: Human polycystin-2 transgene dose-dependently rescues ADPKD phenotypes in Pkd2 mutant mice.
abstract: Although much is known about the molecular genetic mechanisms of autosomal-dominant polycystic kidney disease (ADPKD), few effective treatment is currently available. Here, we explore the in vivo effects of causal gene replacement in orthologous gene models of ADPKD in mice. Wild-type mice with human PKD2 transgene (PKD2(tg)) overexpressed polycystin (PC)-2 in several tissues, including the kidney and liver, and showed no significant cyst formation in either organ. We cross-mated PKD2(tg) with a Pkd2-null mouse model, which is embryonically lethal and forms renal and pancreatic cysts. Pkd2(-/-) mice with human PKD2 transgene (Pkd2(-/-);PKD2(tg)) were born in expected Mendelian ratios, indicating that the embryonic lethality of the Pkd2(-/-) mice was rescued. Pkd2(-/-);PKD2(tg) mice survived up to 12 months and exhibited moderate to severe cystic phenotypes of the kidney, liver, and pancreas. Moreover, Pkd2(-/-) mice with homozygous PKD2(tg)-transgene alleles (Pkd2(-/-);PKD2(tg/tg)) showed significant further amelioration of the cystic severity compared to that in Pkd2(-/-) mice with a hemizygous PKD2(tg) allele (Pkd2(-/-);PKD2(tg)), suggesting that the ADPKD phenotype was improved by increased transgene dosage. On further analysis, cystic improvement mainly resulted from reduced proliferation, rather apoptosis, of cyst-prone epithelial cells in the mouse model. The finding that the functional restoration of human PC2 significantly rescued ADPKD phenotypes in a dose-dependent manner suggests that increasing PC2 activity may be beneficial in some forms of ADPKD.
authors.affiliation: Center of Translational Cancer Research and Therapy, State Key Laboratory of Molecular Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Ao
authors.initials: A
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Xin
authors.initials: X
authors.lastname: Tian
authors.affiliation: Center of Translational Cancer Research and Therapy, State Key Laboratory of Molecular Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Shunwei
authors.initials: S
authors.lastname: Huang
authors.affiliation: Center of Translational Cancer Research and Therapy, State Key Laboratory of Molecular Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Dianqing
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Moeckel
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Stefan
authors.initials: S
authors.lastname: Somlo
authors.affiliation: Center of Translational Cancer Research and Therapy, State Key Laboratory of Molecular Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Medicine, Vanderbilt University, Nashville, Tennessee. Electronic address: guanqing.wu@cicams.ac.cn.
authors.forename: Guanqing
authors.initials: G
authors.lastname: Wu
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D003560:Cysts / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D050396:TRPP Cation Channels / Q000235:genetics*
chemical_list: D050396:TRPP Cation Channels