Department of Biological Sciences, Sookmyung Women's University, Seoul, South Korea.
FASEB J. 2018 Jul;32(7):3574-3582. doi: 10.1096/fj.201700923R. Epub 2018 Feb 16.
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited disorders. ADPKD is caused by mutations in the gene encoding either polycystic kidney disease 1 ( PKD1) or polycystic kidney disease 2 ( PKD2). Patients with ADPKD show progressive growth of cystic fluid-filled renal cysts. Here, we used Pkd2 control mice and Pkd2:HoxB7-Cre experimental mice, which are bred to have a conditional deletion of Pkd2 in the collecting ducts, and analyzed the expression pattern of microRNAs (miRNAs) of kidney tissues from Pkd2 and Pkd2:HoxB7-Cre mice. Decreased expression of miR-20b-5p and miR-106a-5p in Pkd2:HoxB7-Cre mice compared to that in Pkd2 mice was observed. These miRNAs target Klf12 (Krüppel-like factor 12), which has low expression in kidney tissues of Pkd2 mice; however, its expression is enhanced in Pkd2:HoxB7-Cre mice over time. Moreover, miR-20b-5p and miR-106a-5p directly target Klf12 mRNA by binding to the 3'-UTR of Klf12. In addition, human and mouse cell lines exhibit similar patterns. These findings were also consistent with the data from Pkd2 knockout mouse embryonic fibroblasts. Furthermore, direct and indirect knockdown of Klf12 slows cyst growth and cell proliferation in mouse inner medullary collecting duct cells. Taken together, we suggest that the induction of miR-20b-5p or miR-106a-5p or the down-regulation of KLF12 could be used as potential novel therapies for inhibiting cyst growth in patients with ADPKD.-Shin, Y., Kim, D. Y., Ko, J. Y., Woo, Y. M., Park, J. H. Regulation of KLF12 by microRNA-20b and microRNA-106a in cystogenesis.
常染色体显性多囊肾病 (ADPKD) 是最常见的遗传性疾病之一。ADPKD 是由编码多囊肾病 1 (PKD1) 或多囊肾病 2 (PKD2) 的基因突变引起的。ADPKD 患者表现为囊性充满液体的肾囊肿进行性生长。在这里，我们使用 Pkd2 对照小鼠和 Pkd2:HoxB7-Cre 实验小鼠，这些小鼠被培育为在集合管中具有 Pkd2 的条件性缺失，并分析了来自 Pkd2 和 Pkd2:HoxB7-Cre 小鼠的肾组织中小 RNA (miRNA) 的表达模式。与 Pkd2 小鼠相比，Pkd2:HoxB7-Cre 小鼠中 miR-20b-5p 和 miR-106a-5p 的表达降低。这些 miRNA 靶向 Klf12（Krüppel-like factor 12），其在 Pkd2 小鼠的肾组织中表达较低；然而，其表达随时间推移在 Pkd2:HoxB7-Cre 小鼠中增强。此外，miR-20b-5p 和 miR-106a-5p 通过与 Klf12 mRNA 的 3'-UTR 结合直接靶向 Klf12。此外，人和鼠细胞系表现出相似的模式。这些发现也与 Pkd2 敲除鼠胚胎成纤维细胞的数据一致。此外，Klf12 的直接和间接敲低可减缓小鼠内髓集合管细胞中的囊肿生长和细胞增殖。综上所述，我们认为诱导 miR-20b-5p 或 miR-106a-5p 或下调 KLF12 可作为抑制 ADPKD 患者囊肿生长的潜在新疗法。-Shin，Y.，Kim，D. Y.，Ko，J. Y.，Woo，Y. M.，Park，J. H. 微 RNA-20b 和微 RNA-106a 在囊肿发生中的 Klf12 调控。
