Mechanism of Fibrosis in HNF1B-Related Autosomal Dominant Tubulointerstitial Kidney Disease
Mechanism of Fibrosis in HNF1B-Related Autosomal Dominant Tubulointerstitial Kidney Disease
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DOI：
10.1681/asn.2018040437
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发表时间：
2018-10-01
影响因子：
13.6
通讯作者：
Igarashi, Peter
中科院分区：
文献类型：
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作者：
Chan, Siu Chiu;Zhang, Ying;Igarashi, Peter
背景资料：编码转录因子HNF-1 β的基因HNF 1B突变是常染色体显性遗传性肾小管间质性肾病的原因之一，这是一种以肾小管囊肿、肾纤维化和肾功能进行性下降为特征的综合征。HNF-1 β也参与上皮-间质转化（EMT）途径，持续的EMT与组织纤维化相关。突变的HNF-1 B导致肾小管间质纤维化的机制尚不清楚。方法：为了探索纤维化的机制，我们建立了HNF-1 β缺陷的mIMCD 3肾上皮细胞，使用RNA测序分析来揭示野生型和HNF-1 β缺陷的mIMCD 3细胞中差异表达的基因，并在HNF-1 β突变小鼠中进行细胞谱系分析。HNF-1 β缺陷细胞表现出间充质细胞如成纤维细胞的特性，包括纺锤形形态、接触抑制丧失和细胞迁移增加。这些细胞还显示纤维化和EMT途径的上调，包括Twist 2，Snail 1，Snail 2和Zeb 2的上调，这些都是关键的EMT转录因子。从机制上讲，HNF-1 β直接抑制Twist 2，Twist 2的消融部分挽救了HNF-1 β突变细胞的成纤维细胞表型。来自HNF-1 β突变小鼠的肾脏显示Twist 2及其下游靶点Snai 2的表达增加。细胞谱系分析表明，HNF-1 β突变上皮细胞不转分化成肾肌成纤维细胞。相反，HNF-1 β突变的上皮细胞分泌高水平的TGF-β配体，激活下游Smad转录因子在肾间质cells.Conclusions：消融HNF-1 β在肾上皮细胞导致激活的Twist 2依赖的转录网络，诱导EMT和异常的TGF-β信号，导致肾纤维化通过细胞非自主机制。
Background: Mutation of HNF1B, the gene encoding transcription factor HNF-1 beta, is one cause of autosomal dominant tubulointerstitial kidney disease, a syndrome characterized by tubular cysts, renal fibrosis, and progressive decline in renal function. HNF-1 beta has also been implicated in epithelial-mesenchymal transition (EMT) pathways, and sustained EMT is associated with tissue fibrosis. The mechanism whereby mutated HNF1B leads to tubulointerstitial fibrosis is not known.Methods: To explore the mechanism of fibrosis, we created HNF-1 beta-deficient mIMCD3 renal epithelial cells, used RNA-sequencing analysis to reveal differentially expressed genes in wild-type and HNF-1 beta-deficient mIMCD3 cells, and performed cell lineage analysis in HNF-1 beta mutant mice.Results: The HNF-1 beta-deficient cells exhibited properties characteristic of mesenchymal cells such as fibroblasts, including spindle-shaped morphology, loss of contact inhibition, and increased cell migration. These cells also showed upregulation of fibrosis and EMT pathways, including upregulation of Twist2, Snail1, Snail2, and Zeb2, which are key EMT transcription factors. Mechanistically, HNF-1 beta directly represses Twist2, and ablation of Twist2 partially rescued the fibroblastic phenotype of HNF-1 beta mutant cells. Kidneys from HNF-1 beta mutant mice showed increased expression of Twist2 and its downstream target Snai2. Cell lineage analysis indicated that HNF-1 beta mutant epithelial cells do not transdifferentiate into kidney myofibroblasts. Rather, HNF-1 beta mutant epithelial cells secrete high levels of TGF-beta ligands that activate downstream Smad transcription factors in renal interstitial cells.Conclusions: Ablation of HNF-1 beta in renal epithelial cells leads to the activation of a Twist2-dependent transcriptional network that induces EMT and aberrant TGF-beta signaling, resulting in renal fibrosis through a cell-nonautonomous mechanism.