Mechanism of Fibrosis in HNF1B-Related Autosomal Dominant Tubulointerstitial Kidney Disease

Chan, Siu Chiu; Zhang, Ying; Shao, Annie; Avdulov, Svetlana; Herrera, Jeremy; Aboudehen, Karam; Pontoglio, Marco; Igarashi, Peter

doi:10.1681/asn.2018040437

Cited by 55 publications

(61 citation statements)

References 71 publications

(93 reference statements)

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“…Previous studies from our laboratory have shown that ablation of Hnf1b in kidney epithelial cells and kidney-specific knockout of Hnf1b in transgenic mice lead to activation of the canonical Wnt pathway (24). To identify Wnt pathway genes that are directly regulated by HNF-1β, we compared our previous RNA-seq and ChIP-seq datasets (18) and identified Lef1, a downstream effector in the canonical Wnt signaling pathway, as a potential HNF-1β target gene. To determine whether expression of Lef1 is dependent on HNF-1β, we performed quantitative RT-PCR analysis on mIMCD3 cells in which Hnf1b was deleted by CRISPR/Cas9 gene editing (18).…”

Section: Expression Of Lef1 Is Increased In Hnf-mentioning

confidence: 99%

“…To identify Wnt pathway genes that are directly regulated by HNF-1β, we compared our previous RNA-seq and ChIP-seq datasets (18) and identified Lef1, a downstream effector in the canonical Wnt signaling pathway, as a potential HNF-1β target gene. To determine whether expression of Lef1 is dependent on HNF-1β, we performed quantitative RT-PCR analysis on mIMCD3 cells in which Hnf1b was deleted by CRISPR/Cas9 gene editing (18). Under basal conditions, the expression of Lef1 was 4.7-fold higher in HNF-1β-deficient cells compared to wild-type mIMCD3 cells.…”

Section: Expression Of Lef1 Is Increased In Hnf-mentioning

confidence: 99%

“…Collecting ductspecific deletion of Hnf1b produces a more slowly progressive disease and has revealed roles of HNF-1β in urinary concentration and renal fibrosis (17). Transcriptomic analysis of Hnf1b mutant cells suggests that HNF-1β regulates a broad range of genetic networks involving cellular metabolism, cancer, and fibrosis (8,18). Recently, new functions of HNF-1β in the regulation of noncoding RNAs, cholesterol metabolism, and epithelial-mesenchymal transition have been identified (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

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Hepatocyte nuclear factor 1β suppresses canonical Wnt signaling through transcriptional repression of lymphoid enhancer–binding factor 1

Chan

Hajarnis

Vrba

et al. 2020

Journal of Biological Chemistry

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Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcription factor that is required for normal kidney development and renal epithelial differentiation. Mutations of HNF-1β produce congenital kidney abnormalities and inherited renal tubulopathies. Here, we show that ablation of HNF-1β in mIMCD3 renal epithelial cells results in activation of β-catenin and increased expression of lymphoid enhancer-binding factor 1 (LEF1), a downstream effector in the canonical Wnt signaling pathway. Increased expression and nuclear localization of LEF1 are also observed in cystic kidneys from Hnf1b mutant mice. Expression of dominant-negative mutant HNF-1β in mIMCD3 cells produces hyperresponsiveness to exogenous Wnt ligands, which is inhibited by siRNA-mediated knockdown of Lef1. Wild-type HNF-1β binds to two evolutionarily conserved sites located 94 kb and 30 kb from the mouse Lef1 promoter. Ablation of HNF-1β decreases H3K27 trimethylation repressive marks and increases β-catenin occupancy at a site 4 kb upstream to Lef1. Mechanistically, wild-type HNF-1β recruits the polycomb repressive complex 2 that catalyzes H3K27 trimethylation. Deletion of the β-catenin-binding domain of LEF1 in HNF-1β-deficient cells abolishes the increase in Lef1 transcription and decreases the expression of downstream Wnt target genes. The canonical Wnt target gene, Axin2, is also a direct transcriptional target of HNF-1β through binding to negative regulatory elements in the gene promoter. These findings demonstrate that HNF-1β regulates canonical Wnt target genes through long-range effects on histone methylation at Wnt enhancers and reveal a new mode of active transcriptional repression by HNF-1β.

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Section: Expression Of Lef1 Is Increased In Hnf-mentioning

confidence: 99%

Section: Expression Of Lef1 Is Increased In Hnf-mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hepatocyte nuclear factor 1β suppresses canonical Wnt signaling through transcriptional repression of lymphoid enhancer–binding factor 1

Chan

Hajarnis

Vrba

et al. 2020

Journal of Biological Chemistry

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“…EMT is essential for tissue regeneration and, when sustained, is associated with fibrogenesis 33 . Recently, Chan et al found that loss of HNF1b may induce EMT in vitro and in vivo, leading to upregulation of expression of TGF-b ligands in renal epithelial cells, which can ultimately cause renal fibrosis 34 . These findings reveal a potential novel mechanism of renal fibrosis in HNF1B-nephropathy 2,34. The second important finding of our study was that cystic disease was the predominant renal imaging phenotype, being found in 92% of patients (see Table 3).…”

Section: Discussionmentioning

confidence: 99%

Variable Expressivity of HNF1B Nephropathy, From Renal Cysts and Diabetes to Medullary Sponge Kidney Through Tubulo-interstitial Kidney Disease

Izzi

Dordoni

Econimo

et al. 2020

Kidney International Reports

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…Recent studies have identi ied 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 disease [15][16][17].…”

Section: Discussionmentioning

confidence: 99%

Diabetes and chronic kidney disease: a rare cause for a very common association

Fonseca¹,

Jorge²,

Gameiro³

et al. 2019

J Clini Nephrol

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The authors present the case of a 45-year-old female patient with diabetes and chronic kidney disease (CKD). She had unsatisfactory glycemic control, and showed some intellectual limitations. Her urine exam was unremarkable, and her renal ultrasound revealed single right kidney with aspects suggesting ureteropelvic junction syndrome. Her mother had also suffered from diabetes and CKD G5D presenting in the sixth to seventh decade.An hereditary cause for CKD was considered, which led the authors to investigate an autosomal dominant cause for CKD with a tubulointerstitial phenotype, taking into account the personal and family history for diabetes and also the renal imaging; a large deletion in the HNF-1β gene was identifi ed through Multiplex Ligand Probe Assay (MLPA) analysis, explaining the phenotype.Genetic causes of CKD should be considered in the presence of positive family history for CKD, and the coexistence of diabetes with bland urine sediment should raise the possibility of a syndromic cause of the phenotype, namely involving HNF-1β gene mutations or deletions.

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Mechanism of Fibrosis in HNF1B-Related Autosomal Dominant Tubulointerstitial Kidney Disease

Abstract: Ablation of HNF-1 in renal epithelial cells leads to the activation of a Twist2-dependent transcriptional network that induces EMT and aberrant TGF- signaling, resulting in renal fibrosis through a cell-nonautonomous mechanism.

Cited by 55 publications

References 71 publications

Hepatocyte nuclear factor 1β suppresses canonical Wnt signaling through transcriptional repression of lymphoid enhancer–binding factor 1

Hepatocyte nuclear factor 1β suppresses canonical Wnt signaling through transcriptional repression of lymphoid enhancer–binding factor 1

Variable Expressivity of HNF1B Nephropathy, From Renal Cysts and Diabetes to Medullary Sponge Kidney Through Tubulo-interstitial Kidney Disease

Diabetes and chronic kidney disease: a rare cause for a very common association

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