Human Polycystin-2 Transgene Dose-Dependently Rescues ADPKD Phenotypes in Pkd2 Mutant Mice
Human Polycystin-2 Transgene Dose-Dependently Rescues ADPKD Phenotypes in Pkd2 Mutant Mice
复制标题
人多囊蛋白 2 转基因剂量依赖性地挽救 Pkd2 突变小鼠的 ADPKD 表型。
DOI：
10.1016/j.ajpath.2015.06.014
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发表时间：
2015-10-01
影响因子：
6
通讯作者：
Wu, Guanqing
中科院分区：
文献类型：
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作者：
Li, Ao;Tian, Xin;Wu, Guanqing
虽然对常染色体显性多囊肾病（ADPKD）的分子遗传机制了解很多，但目前很少有有效的治疗方法。在这里，我们探讨了因果基因替换在小鼠ADPKD的同源基因模型中的体内效应。携带人类PKD2转基因（PKD2(tg)）的野生型小鼠在包括肾脏和肝脏在内的多个组织中过表达多囊素(PC)-2，但在这两个器官中均未出现明显的囊肿形成。我们将PKD2（tg）与PKD2缺失的小鼠模型杂交，该模型具有胚胎致死性并形成肾脏和胰腺囊肿。人Pkd2（-/-）转基因小鼠Pkd2(-/-)；PKD2(tg))以预期的孟德尔比例出生，表明PKD2（-/-）小鼠的胚胎致命性得到了挽救。Pkd2 (- / -);PKD2（tg）小鼠存活长达12个月，并表现出中度至重度肾、肝和胰腺囊性表型。此外，具有纯合子Pkd2(tg)-转基因等位基因的Pkd2（-/-）小鼠(Pkd2(-/-)；与具有半合子PKD2（tg）等位基因(PKD2（-/-）的PKD2（-/-）小鼠相比，PKD2（-/-）小鼠的囊性严重程度进一步显著改善；PKD2(tg))，表明增加转基因剂量可改善ADPKD表型。进一步分析，囊性改善主要是由于小鼠模型中易囊肿上皮细胞增殖减少，而不是凋亡。人类PC2的功能恢复以剂量依赖的方式显著拯救了ADPKD表型，这一发现表明，增加PC2活性可能对某些形式的ADPKD有益。
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.