Adamts1 Promotes Cyst Expansion in Polycystic Kidney Disease
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ABSTRACT:
PROVIDER: PRJNA1127459 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29530171.fastq.gz | Fastqsanger.gz | |||
| SRR29530172.fastq.gz | Fastqsanger.gz | |||
| SRR29530173.fastq.gz | Fastqsanger.gz | |||
| SRR29530174.fastq.gz | Fastqsanger.gz | |||
| SRR29530175.fastq.gz | Fastqsanger.gz |
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Project description:Autosomal dominant polycystic kidney disease (ADPKD) is characterized by mutations in either the PKD1 or PKD2 genes leading to progressive cyst growth and often ESKD. We have previously demonstrated that with loss of Pkd1 the tubules can enlarge without an increase in tubular cell numbers, suggesting that tubular basement membrane remodeling is important for cystic dilation. Here we compared the transcriptomes from inducible tubule-specific knock out of Pkd1 (PkdTKO) and the uninduced littermate mice kidneys as controls. RNA sequencing revealed significant upregulation of 17 metalloproteinases. Of these, A Disintegrin and Metalloproteinase with Thrombospondin Motif 1 (Adamts1), expressed primarily by the proximal tubule, is the most significantly upregulated following loss of Pkd1 expression. Upregulation of Adamts1 in PkdTKO kidneys correlated with a significant increase in the 70 kDa cleavage product of the V1 isoform of versican, which localized to the tubule basement membrane (TBM) and adjacent interstitial mononuclear cells. Simultaneous deletion of both Adamts1 and Pkd1 (P/ATKO) reduced Adamts1 expression levels by >90%, prevented V1 versican cleavage, and reduced interstitial macrophage accumulation and activation. P/ATKO mice demonstrated slower cystic enlargement, improved BUN and creatinine and better survival than did PkdTKO mice. In conclusion, preventing Adamts1 upregulation following loss of tubular Pkd1 expression effectively reduced macrophage accumulation and TBM remodeling, slowing cyst growth and preserving renal function.
2024-09-30 | GSE270531 | GEO
Project description:DNMT1 promotes cyst growth and epigenetic age acceleration in autosomal dominant polycystic kidney disease
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Project description:To elucidate the molecular pathways that modulate renal cyst growth in autosomal dominant polycystic kidney disease (ADPKD) Keywords: Disease state analysis
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Project description:Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and
PKD2, encoding polycystin-1 (PC1) and polycystin-2 (PC2), which are required for the regulation
of the renal tubular diameter. Loss of polycystin function results in cyst formation. Atypical forms
of ADPKD are caused by mutations in genes encoding endoplasmic reticulum (ER)-resident
proteins through mechanisms that are not well understood. Here, we investigate the function of
DNAJB11, an ER co-chaperone associated with atypical ADPKD. We generated mouse models with
constitutive and conditional Dnajb11 inactivation and Dnajb11-deficient renal epithelial cells to
investigate the mechanism underlying autosomal dominant inheritance, the specific cell types
driving cyst formation, and molecular mechanisms underlying DNAJB11-dependent polycystic
kidney disease. We show that biallelic loss of Dnajb11 causes cystic kidney disease and fibrosis,
mirroring human disease characteristics. In contrast to classical ADPKD, cysts predominantly
originate from proximal tubules. Cyst formation begins in utero and the timing of Dnajb11
inactivation strongly influences disease severity. Furthermore, we identify impaired PC1 cleavage
as a potential mechanism underlying DNAJB11-dependent cyst formation. Proteomic analysis of
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Project description:Autosomal dominant polycystic kidney disease (ADPKD) is caused by muta1ons in PKD1 and
PKD2, encoding polycystin-1 (PC1) and polycystin-2 (PC2), which are required for the regula1on
of the renal tubular diameter. Loss of polycystin func1on results in cyst forma1on. Atypical forms
of ADPKD are caused by mutations in genes encoding endoplasmic reticulum (ER)-resident
proteins through mechanisms that are not well understood. Here, we investigate the func1on of
DNAJB11, an ER co-chaperone associated with atypical ADPKD. We generated mouse models with
constitutive and conditional Dnajb11 inactivation and Dnajb11-deficient renal epithelial cells to
investigate the mechanism underlying autosomal dominant inheritance, the specific cell types
driving cyst formation, and molecular mechanisms underlying DNAJB11-dependent polycystic
kidney disease. We show that biallelic loss of Dnajb11 causes cystic kidney disease and fibrosis,
mirroring human disease characteristics. In contrast to classical ADPKD, cysts predominantly
originate from proximal tubules. Cyst formation begins in utero and the timing of Dnajb11
inactivation strongly influences disease severity. Furthermore, we identify impaired PC1 cleavage as a potential mechanism underlying DNAJB11-dependent cyst formation. Proteomic analysis of Dnajb11- and Pkd1-deficient cells reveals common and distinct pathways and dysregulated proteins, providing a foundation to better understand phenotypic differences between different forms of ADPKD.
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Project description:Background: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Methods: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Results: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Conclusions: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways.
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Project description:To elucidate the molecular pathways that modulate renal cyst growth in autosomal dominant polycystic kidney disease (ADPKD) Keywords: Disease state analysis We performed global gene profiling on renal cysts of different size (small cysts: less than 1 ml, n=5; medium cysts: between 10-25 ml, n=5; large cysts: greater than 50 ml, n=3) and minimally cystic tissue (MCT, n=5) from five PKD1 polycystic kidneys. Additionally, non-cancerous renal cortical tissue from three nephrectomized kidneys with isolated renal cell carcinoma was used as normal control tissue (n=3). This dataset is part of the TransQST collection.
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Project description:Polycystic Kidney Disease (PKD) is a genetic disease of the kidney characterized by the gradual replacement of normal kidney parenchyma by fluid-filled cysts and fibrotic tissue. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in the PKD1 or PKD2 gene. Here we present an RNASeq experiment designed to investigate the effect of a kidney specific and Tamoxifen inducible knockout of the Pkd1 gene in mice. The Pkd1cko mice were harvested at different time points 2-weeks, 3-weeks, 5-weeks, 10.5-weeks, 11-weeks and 15-weeks after gene inactivation.
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