Expression of Renal Cystic Genes in Patients with &lt;i&gt;HNF1B &lt;/i&gt;Mutations

Faguer, Stanislas; Decramer, Stéphane; Devuyst, Olivier; Lengelé, Jean-Philippe; Fournié, Gilbert J.; Chauveau, Dominique

doi:10.1159/000334954

Cited by 9 publications

(9 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These findings led to the hypothesis that the renal phenotype in HNF1B mutant carriers could be attributed to the global inhibition of these cystic genes. However, analyses of fetuses carrying two different HNF1B mutations ( Haumaitre et al, 2006 ) as well as of adult mutant carriers ( Faguer et al, 2012 ) show that the cystic renal phenotype was not associated with decreased expression of the cystic disease genes identified in mice, implying that a more complex HNF1B transcriptional network underlies the human disease.…”

Section: Introductionmentioning

confidence: 99%

Hnf1b haploinsufficiency differentially affects developmental target genes in a new renal cysts and diabetes mouse model

Niborski

Paces-Fessy

Ricci

et al. 2021

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

Heterozygous mutations in HNF1B cause the complex syndrome Renal Cysts and Diabetes (RCAD), characterized by developmental abnormalities of the kidneys, genital tracts and pancreas, and a variety of renal, pancreas and liver dysfunctions. The pathogenesis underlying this syndrome remains unclear as mice with heterozygous null mutations have no phenotype, while constitutive/conditional Hnf1b-ablation leads to more severe phenotypes.We generated a novel mouse model carrying an identified human mutation at the intron-2 splice donor-site. Unlike heterozygous previously characterized, heterozygous for the splicing mutation exhibited decreased HNF1B protein levels and bilateral renal cysts from embryonic stage E15, originated from glomeruli, early proximal tubules (PT) and intermediate nephron segments, concurrently with a delayed PT differentiation, hydronephrosis and rare genital tract anomalies.Consistently, mRNA-sequencing showed that most down-regulated genes in embryonic kidneys were primarily expressed in early PTs and Henle's Loop and involved in ion/drug transport, organic acid and lipid metabolic processes, while the expression of previously identified targets upon Hnf1b-ablation, including cystic disease genes was weakly or not affected. Postnatal analyses revealed renal abnormalities, ranging from glomerular cysts to hydronephrosis and rarely multicystic dysplasia. Urinary proteomics uncovered a particular profile predictive of progressive decline in kidney function and fibrosis, and displayed common features with a recently reported urine proteome in a RCAD pediatric cohort. Altogether our results show that HNF1B reduced levels lead to developmental disease phenotypes associated with the deregulation of a subset of its targets. They further suggest that this model represents a unique clinical/pathological viable model of the RCAD disease.

show abstract

Section: Introductionmentioning

confidence: 99%

Hnf1b haploinsufficiency differentially affects developmental target genes in a new renal cysts and diabetes mouse model

Niborski

Paces-Fessy

Ricci

et al. 2021

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

show abstract

“…35 Subsequent work has confirmed that measuring mRNA expression in urinary sediment can be a useful approach to assess the renal epithelial transcriptome in HNF1B-associated renal disease. 36 The role of HNF1B in renal development HNF1B is widely expressed in multiple fetal tissues and is required for visceral endoderm specification. 37 HNF1A is expressed later than HNF1B and is activated only during organogenesis.…”

Section: Introductionmentioning

confidence: 99%

HNF1B-associated renal and extra-renal disease—an expanding clinical spectrum

Hamilton²,

et al. 2014

View full text Add to dashboard Cite

Heterozygous mutations in the gene that encodes the transcription factor hepatocyte nuclear factor 1β (HNF1B) represent the most common known monogenic cause of developmental kidney disease. Renal cysts are the most frequently detected feature of HNF1B-associated kidney disease; however, other structural abnormalities, including single kidneys and renal hypoplasia, and electrolyte abnormalities can also occur. Extra-renal phenotypes might also be observed; consequently, HNF1B-associated disease is considered a multi-system disorder. Other clinical features include early-onset diabetes mellitus, pancreatic hypoplasia, genital tract malformations, abnormal liver function and early-onset gout. Heterozygous mutations in the coding region or splice sites of HNF1B, and complete gene deletion, each account for ∼50% of all cases of HNF1B-associated disease, respectively, and often arise spontaneously. There is no clear genotype-phenotype correlation, consistent with haploinsufficiency as the disease mechanism. Data from animal models suggest that HNF1B has an important function during several stages of nephrogenesis; however, the precise signalling pathways remain to be elucidated. This Review discusses the genetics and molecular pathways that lead to disease development, summarizes the reported renal and extra-renal phenotypes, and identifies areas for future research in HNF1B-associated disease.

show abstract

“…HNF-1β expression begins during the initial step of the developmental stage of the kidneys and continues to be expressed into adulthood, although this expression is then restricted to the epithelial cells [ 29 , 30 ]. Defective HNF-1β target genes caused by HNF1B mutation, including polycystin (Pkd2), polyductin (Pkhd1), and uromodulin (Umod), lead to the loss of orientation of the mitotic spindles in the renal epithelial cells during tubular elongation, resulting in the formation of renal cysts (polycystic kidney disease) [ 31 ]. In contrast, we found that HNF-1β induced the re-epithelialization of hRPTECs dedifferentiated by TGF-β1, which plays a pivotal role in the pathogenesis of renal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte Nuclear Factor-1β Induces Redifferentiation of Dedifferentiated Tubular Epithelial Cells

et al. 2016

View full text Add to dashboard Cite

Tubular epithelial cells (TECs) can be dedifferentiated by repetitive insults, which activate scar-producing cells generated from interstitial cells such as fibroblasts, leading to the accumulation and deposition of extracellular matrix molecules. The dedifferentiated TECs play a crucial role in the development of renal fibrosis. Therefore, renal fibrosis may be attenuated if dedifferentiated TECs are converted back to their normal state (re-epithelialization). However, the mechanism underlying the re-epithelialization remains to be elucidated. In the present study, TGF-β1, a profibrotic cytokine, induced dedifferentiation of cultured TECs, and the dedifferentiated TECs were re-epithelialized by the removal of TGF-β1 stimulation. In the re-epithelialization process, transcription factor hepatocyte nuclear factor 1, beta (HNF-1β) was identified as a candidate molecule involved in inducing re-epithelialization by means of DNA microarray and biological network analysis. In functional validation studies, the re-epithelialization by TGF-β1 removal was abolished by HNF-1β knockdown. Furthermore, the ectopic expression of HNF-1β in the dedifferentiated TECs induced the re-epithelialization without the inhibition of TGF-β/Smad signaling, even in the presence of TGF-β1 stimulation. In mouse renal fibrosis model, unilateral ureteral obstruction model, HNF-1β expression in the TECs of the kidney was suppressed with fibrosis progression. Furthermore, the HNF-1β downregulated TECs resulted in dedifferentiation, which was characterized by expression of nestin. In conclusion, HNF-1β suppression in TECs is a crucial event for the dedifferentiation of TECs, and the upregulation of HNF-1β in TECs has a potential to restore the dedifferentiated TECs into their normal state, leading to the attenuation of renal fibrosis.

show abstract

Expression of Renal Cystic Genes in Patients with <i>HNF1B </i>Mutations

Cited by 9 publications

References 59 publications

Hnf1b haploinsufficiency differentially affects developmental target genes in a new renal cysts and diabetes mouse model

Hnf1b haploinsufficiency differentially affects developmental target genes in a new renal cysts and diabetes mouse model

HNF1B-associated renal and extra-renal disease—an expanding clinical spectrum

Hepatocyte Nuclear Factor-1β Induces Redifferentiation of Dedifferentiated Tubular Epithelial Cells

Contact Info

Product

Resources

About