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Abstract：
Hepatocyte nuclear factor 1β (HNF1β) is a transcription factor essential for the development and function of the kidney. Mutations in and deletions of HNF1β cause autosomal dominant tubule interstitial kidney disease (ADTKD) subtype HNF1β, which is characterized by renal cysts, diabetes, genital tract malformations, and neurodevelopmental disorders. Electrolyte disturbances including hypomagnesemia, hyperuricemia, and hypocalciuria are common in patients with ADTKD-HNF1β. Traditionally, these electrolyte disturbances have been attributed to HNF1β-mediated transcriptional regulation of gene networks involved in ion transport in the distal part of the nephron including FXYD2, CASR, KCNJ16, and FXR. In this review, we propose additional mechanisms that may contribute to the electrolyte disturbances observed in ADTKD-HNF1β patients. Firstly, kidney development is severely affected in Hnf1b-deficient mice. HNF1β is required for nephron segmentation, and the absence of the transcription factor results in rudimentary nephrons lacking mature proximal tubule, loop of Henle, and distal convoluted tubule cluster. In addition, HNF1β is proposed to be important for apical-basolateral polarity and tight junction integrity in the kidney. Interestingly, cilia formation is unaffected by Hnf1b defects in several models, despite the HNF1β-mediated transcriptional regulation of many ciliary genes. To what extent impaired nephron segmentation, apical-basolateral polarity, and cilia function contribute to electrolyte disturbances in HNF1β patients remains elusive. Systematic phenotyping of Hnf1b mouse models and the development of patient-specific kidney organoid models will be essential to advance future HNF1β research.
摘要：
肝细胞核因子1β（HNF1β）是肾脏发育和功能必需的转录因子。HNF1β的突变和缺失导致常染色体显性肾小管间质性肾病（ADTKD）亚型HNF1β，以肾囊肿为特征，糖尿病,生殖道畸形,和神经发育障碍。电解质紊乱包括低镁血症，高尿酸血症,ADTKD-HNF1β患者常见低钙尿症。传统上,这些电解质紊乱已归因于HNF1β介导的基因网络的转录调节参与肾单位远端部分的离子转运，包括FXYD2，CASR，KCNJ16和FXR。在这次审查中,我们提出了可能导致ADTKD-HNF1β患者电解质紊乱的其他机制.首先,Hnf1b缺陷小鼠的肾脏发育受到严重影响。肾单位分割需要HNF1β，转录因子的缺失导致缺乏成熟近端小管的基本肾单位，Henle的循环,和远曲小管簇。此外,HNF1β被认为对肾脏的顶端-基底外侧极性和紧密连接完整性很重要。有趣的是,在几个模型中，纤毛的形成不受Hnf1b缺陷的影响，尽管HNF1β介导的许多纤毛基因的转录调控。在多大程度上损害了肾单位分割，顶端-基底外侧极性，和纤毛功能有助于HNF1β患者的电解质紊乱仍然难以捉摸。Hnf1b小鼠模型的系统表型分析和患者特异性肾脏类器官模型的开发对于推进未来的HNF1β研究至关重要。
