New insights into the role of HNF-1β in kidney (patho)physiology.
New insights into the role of HNF-1β in kidney (patho)physiology.
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DOI：
10.1007/s00467-018-3990-7
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发表时间：
2019-08
期刊：
影响因子：
--
通讯作者：
Igarashi P
中科院分区：
文献类型：
--
作者：
Ferrè S;Igarashi P
肝细胞核因子-1 β（hepatocyte nuclear factor-1 β，HNF-1β）是调节肾、肝、胰腺和泌尿生殖道上皮细胞发育和功能的重要转录因子。携带HNF 1B突变的人会发生异质性肾脏异常，包括多囊性发育不良肾、肾小球囊性肾病、肾发育不全、肾发育不全和肾间质纤维化。在胚胎肾中，HNF-1β是输尿管芽分支、肾发生起始和肾单位分割所必需的。在肾单位祖细胞中的小鼠Hnf 1b的消融导致有缺陷的小管发生，而后来在伸长小管中的失活导致囊肿形成，这是由于囊性疾病基因的下调，包括Umod，Pkhd 1和Pkd 2。在成人肾脏中，HNF-1β控制肾小管上皮细胞肾内代谢和溶质转运所需基因的表达。在HNF-1β肾病中观察到的肾小管异常包括高尿酸血症伴或不伴痛风、低钾血症、低镁血症和多尿。最近的研究发现了新的转录后和翻译后调控机制，包括miRNA簇miR 17 ~92和相互作用蛋白PCBD 1和zyxin。进一步了解HNF-1β上游和下游的分子机制可能会导致囊性肾病和其他HNF-1B相关肾脏疾病的新治疗方法的发展。
Hepatocyte nuclear factor-1β (HNF-1β) is an essential transcription factor that regulates the development and function of epithelia in the kidney, liver, pancreas, and genitourinary tract. Humans who carry HNF1B mutations develop heterogeneous renal abnormalities, including multicystic dysplastic kidneys, glomerulocystic kidney disease, renal agenesis, renal hypoplasia, and renal interstitial fibrosis. In the embryonic kidney, HNF-1β is required for ureteric bud branching, initiation of nephrogenesis, and nephron segmentation. Ablation of mouse Hnf1b in nephron progenitors causes defective tubulogenesis, whereas later inactivation in elongating tubules leads to cyst formation due to downregulation of cystic disease genes, including Umod, Pkhd1, and Pkd2. In the adult kidney, HNF-1β controls the expression of genes required for intrarenal metabolism and solute transport by tubular epithelial cells. Tubular abnormalities observed in HNF-1β nephropathy include hyperuricemia with or without gout, hypokalemia, hypomagnesemia, and polyuria. Recent studies have identified novel post-transcriptional and post-translational regulatory mechanisms that control HNF-1β expression and activity, including the miRNA cluster miR17~92 and the interacting proteins PCBD1 and zyxin. Further understanding of the molecular mechanisms upstream and downstream of HNF-1β may lead to the development of new therapeutic approaches in cystic kidney disease and other HNF1B-related renal diseases.
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