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首页> 外文期刊>American Journal of Physiology >Transcription factor HNF1β regulates expression of the calcium-sensing receptor in the thick ascending limb of the kidney
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Transcription factor HNF1β regulates expression of the calcium-sensing receptor in the thick ascending limb of the kidney

机译：转录因子HNF1β调节肾脏上升肢体中钙传感受体的表达

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Mutations in hepatocyte nuclear factor 1β (HNF1β) cause autosomal dominant tubulointerstitial kidney disease (ADTKD-HNF1β), and patients tend to develop renal cysts, maturity-onset diabetes of the young (MODY), and suffer from electrolyte disturbances, including hypomagnesemia, hypokalemia, and hypocalciuria. Previous HNF1β research focused on the renal distal convoluted tubule (DCT) to elucidate the ADTKD-HNF1β electrolyte phenotype, although 70% of Mg2+ is reabsorbed in the thick ascending limb of Henle’s loop (TAL). An important regulator of Mg2+ reabsorption in the TAL is the calcium-sensing receptor (CaSR). This study used several methods to elucidate the role of HNF1β in electrolyte reabsorption in the TAL. HNF1β ChIP-seq data revealed a conserved HNF1β binding site in the second intron of the CaSR gene. Luciferase-promoter assays displayed a 5.8-fold increase in CaSR expression when HNF1β was present. Expression of the HNF1β p.Lys156Glu mutant, which prevents DNA binding, abolished CaSR expression. Hnf1β knockdown in an immortalized mouse kidney TAL cell line (MKTAL) reduced expression of the CaSR and Cldn14 (claudin 14) by 56% and 48%, respectively, while Cldn10b expression was upregulated 5.0-fold. These results were confirmed in a kidney-specific HNF1β knockout mouse, which exhibited downregulation of the Casr by 81%. Cldn19 and Cldn10b expression levels were also decreased by 37% and 83%, respectively, whereas Cldn3 was upregulated by 4.6-fold. In conclusion, HNF1β is a transcriptional activator of the CaSR. Consequently, patients with HNF1β mutations may have reduced CaSR activity in the kidney, which could explain cyst progression and hyperabsorption of Ca2+ and Mg2+ in the TAL resulting in hypocalciuria.
机译：肝细胞核因子1β（HNF1β）的突变引起常染色体显性细胞间肾病（ADTKD-HNF1β），患者倾向于开发肾囊肿，年轻（型染色）的成熟型糖尿病，并患有电解质扰动，包括低钾血症，低恶血症，和低钙尿。以前的HNF1β研究集中在肾远端卷积小管（DCT）上，以阐明ADTKD-HNF1β电解质表型，尽管70％的MG2 +被重新吸收到Henle循环（TAL）的厚度上升肢体中。 Mg2 +重吸收的重要调节剂是钙传感受体（Casr）。该研究使用了几种方法来阐明HNF1β在Tal中电解质重吸收中的作用。 HNF1β芯片-SEQ数据显示了CasR基因的第二内含子中的保守HNF1β结合位点。当存在HNF1β时，荧光素酶 - 启动子测定显示在CasR表达中增加了5.8倍。 HNF1βPLYS156GLU突变体的表达，其防止DNA结合，废除胱大肠杆菌表达。 HNF1β在永生化的小鼠肾脏TAL细胞系（MKTAL）中敲低分别将CASR和CLDN14（CLAUDIN 14）的表达降低56％和48％，而CLDN10B表达被上调5.0倍。这些结果在肾特异性HNF1β敲除小鼠中证实，其在钙的下调将CasR下调81％。 CLDN19和CLDN10B表达水平也分别降低了37％和83％，而CLDN3升高4.6倍。总之，HNF1β是CASR的转录活化剂。因此，HNF1β突变的患者可能在肾脏中减少CASR活性，这可以解释在TAL中的CA2 +和MG2 +的囊性进展和过度升高。

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